Isoxazolyl-substituted perhydrobenzindenes

ABSTRACT

6[(4-Isoxazolyl)-methyl]perhydro-1H-benz[e]indenes, useful for the preparation of pharmaceutically valuable 19-norsteroids and estranes by degradation of the isoxazolylmethylene moiety followed by cyclization, is disclosed.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of Ser. No. 278,889, filed Aug. 9,1972, now abandoned, which in turn is a divisional of Ser. No, 39,560,now U.S. Pat. No. 3,691,190, which in turn is a continuation-in-part ofSer. No. 778,314, now U.S. Pat. No. 3,700,661.

BACKGROUND OF THE INVENTION

In recent years, much effort has been devoted to the total synthesis ofsteroids. The medicinally important 19-norsteroids have been the subjectof a large number of chemical investigations, cf. D. Djerassi, Science,151, 1055 (1966); L. Velluz et al., Tetrahedron Supplement 8, Part II,495 (1966). 19-Norsteroids have been prepared in accordance with priorart teachings by the reduction of Ring A aromatic steroids eitherchemically [A. L. Wilds et al., J. Am. Chem. Soc. 75, 5366 (1953)] orphotolytically [J. A. Waters et al., J. Am. Chem. Soc. 89, 1022 (1967)].Other methods known in the art for the preparation of 19-norsteroidsinclude oxidation of the C-19 methyl group of a steroid to thecorresponding carboxylic acid followed by acidic decarboxylation of theresulting 19-carboxy-Δ⁴ -3-keto system. [A. Bowers et al., J. Am. Chem.Soc. 84, 3204 (1962)].

The present invention relates to certain polycyclic compounds andprocesses for their synthesis. The novel intermediates and processes ofthis invention provide a new synthetic route for the preparation ofpharmaceutically valuable 19-nor-steroids. Further, the intermediatesand processes of the invention provide a novel route for the preparationof pharmaceutically valuable estrones. In synthesis of steroidalmaterials, steric considerations are of great significance. The mostused steroidal compounds are those having a C/D-trans-ring junction withthe substituent in the 13-position being in the β-configuration. Thepresent invention provides a facile total synthesis of 13.sub.β-C/D-trans-steroidal materials. This desirable result is obtained via aunique asymmetric induction followed by subsequent stereospecificreaction steps.

SUMMARY OF THE INVENTION

A 3,5-disubstituted-4-isoxazolylmethylene group is employed as aprecursor of the steroidal Ring A in this synthesis. The novel use ofthis group as a precursor of the steroidal Ring A provides an improvedmethod for obtaining extremely high yields of optically activepharmaceutically valuable steroid end-products. This is in part due tothe chemically stable nature of the isoxazole group to the acids, bases,hydrogenations and other process perameters employed throughout thesynthesis. By-product formation has been substantially reduced by theprocesses of this invention, thereby facilitating costly separating andpurifying procedures. The substantial elimination of by-productformation also contributes to the obtention of the high end-productyields. Further, it has been found that by means of the resolutions ofstarting materials and subsequent stereospecific reaction steps of theprocesses of this invention, the direct obtention of optically activeend-products is greatly facilitated.

In one aspect, this invention relates to substituted-isoxazole startingmaterials of formulae II-a and II-b, intermediates therefor and theirmethod of preparation via a Wittig-type reaction of a phosphonium ylidof formula D and acrolein dimer (formula E) in accordance with ReactionSchemes A and B.

In Reaction Schemes A and B, R₁₅ is selected from the group consistingof lower alkyl and hydrogen; R₁₆ is selected from the group consistingof lower alkyl, lower alkylaryl, aralkyl and hydrogen; X' is aninorganic anion derived from a mineral acid; R'₁, R'₂ and R'₃ areindependently selected from the group consisting of lower alkyl phenyland phenyl-lower alkyl; R₁₇ is selected from the group consisting ofmono-hydrocarbylamino and di-hydrocarbylamino and acid salts thereof;R₁₀ is lower alkyl; R_(A) is selected from the formulae R'_(a) NH andR'_(a) O wherein R'_(a) is an optically active hydrocarbyl residue.##SPC1##

wherein R₁₅, R₁₀, X', R₁ ', R₂ ', and R₃ ' are defined as aforesaid##SPC2##

wherein R_(A), R₁₀, R₁₅, R₁₀, R₁ ', R₂ ', R₃ ' and R₁₇ are defined asaforesaid.

In another aspect, this invention is directed to the process andcompounds represented schematically in Reaction Scheme C. Thus, the3-substituted-6aβ-alkyl-cyclopenta[f][1]-benzopyrans ornaptho[2,1-b]pyrans of formula I-a are prepared by reacting a9-(3,5-substituted-4-isoxazolyl)-7-hydroxy-1-nonen-3-one of the formulaII-a or a tetrahydropyran-2-ol variant thereof of the formula II-b witha 2-lower alkyl cycloalkane-1,3-dione of the formula III. The3aβ-alkyl-7-oxo-1H-benz[e]indenes and 8aβ-alkyl-3H-phenanthren-2-ones ofthe formula XI are prepared by cyclizing the 4- or5-(3-oxo-alkyl)-perhydroindene-5-ones and perhydronaphthalene-6-ones offormula X which are obtained by oxidizing the pyrans of formula I-c. Thelatter perhydropyran intermediates are prepared by saturating the doublebond of the diene of formula I-a and introducing R₂ O (defined below) atthe 4a-position and a hydrogen atom at the 9b-or 10a-position of monoene1-b.

Alternatively, the compounds of formula XI are prepared by alkylation(not shown in Reaction Scheme C) of a 3aβ-alkyl-7-oxo-7H-benz[e]indeneor 8aβ-alkyl-3H-phenanthren-2-one with a 3,5-disubstituted-4-halomethylisoxazole.

In Reaction Scheme C, Y is a substituted isoxazole of the formula##SPC3##

wherein R₁₇, R₁₅ and R₁₀ are defined as aforesaid; R₁ is a primary alkylgroup of from 1 to 5 carbon atoms; R₂ is selected from the groupconsisting of hydrogen, lower primary alkyl or lower acyl; Z is selectedfrom the group consisting of carbonyl, lower alkylenedioxy-methylene,di-lower alkoxy-methylene, phendioxy-methylene and a group of theformula ##STR1## wherein R₇ is selected from the group consisting ofhydrogen, lower alkyl, lower alkoxy-lower alkyl, phenyl-lower alkyl,tetrahydropyranyl and lower acyl; R₃ is selected from the groupconsisting of hydrogen and lower aliphatic hydrocarbyl; and m is aninteger having a value from 1 to 2. pg,8 ##SPC4##

wherein Y, R₁₇, R₁, R₂, Z and m are as defined aforesaid.

A still further aspect of this invention relates to the process andintermediate compounds employed to convert the benz[e]indenes andphenanthren-2-ones of formula XI in accordance with Reaction Schemes Dand D' to 19-nor-steroids of the formula XIV-a, wherein R₁₅, R₁₆, R₁, Zand m are as defined as aforesaid and X is selected from the groupconsisting of lower alkylenedioxy-methylene, phendioxy-methylene,di-lower alkoxy-methylene, the monothia, monoaza or dithia chalcogenthereof and a group of the formula ##STR2## R'₁₅ is selected from thegroup consisting of hydrogen and lower alkyl; Z' is selected from thegroup consisting of carbonyl and a group of the formula W is selectedfrom the group consisting of carbonyl and a group of the formula##STR3## Z" is selected from the group consisting of loweralkylenedioxy-methylene, phendioxy-methylene, di-lower alkoxy-methylene,the monothia, monoaza or dithia chalcogen thereof and a group of theformula ##STR4## R₇ and R₈ are defined as aforesaid and R₇ ' is selectedfrom the group consisting of hydrogen, lower alkyl, lower alkoxy-loweralkyl, phenyl-lower alkyl and tetrahydropyranyl. ##SPC5##

wherein W, R₁, R₁₅, R₁₆, Z, Z', R'₁₅ and m are defined aforesaid##SPC6##

wherein X, R₁, R₁₅, R₁₆, Z, Z", R'₁₅ and m are defined aforesaid

Yet another aspect of this invention relates to the conversion of, vianovel intermediates, the benz[e]indenes and phenanthren-2-ones of theformula XI-a, in accordance with Reaction Scheme E, to the dienones offormula XXXV wherein R₁₅, R'₁₅, W, X, R₁₆, Z, Z" and m are as definedaforesaid and V is selected from the group consisting of loweralkylenedioxy-methylene, di-lower alkoxy-methylene andphendioxy-methylene. ##SPC7##

wherein R'₁₅, W, Z", R₁, R₁₅, X, V, and m are defined as aforesaid.

DETAILED DESCRIPTION OF THE INVENTION

As used throughout the specification and appended claims, the term"hydrocarbyl group" denotes a monovalent substituent consisting solelyof carbon and hydrogen; the term "hydrocarbylene" denotes a divalentsubstituent consisting solely of carbon and hydrogen and having itsvalence bonds from different carbons; the term "aliphatic", withreference to hydrocarbyl or hydrocarbylene groups, denotes groupscontaining no aromatic unsaturation, but which can be otherwisesaturated or unsaturated, i.e., an alkyl or alkylene, or an aliphaticgroup containing olefinic or acetylenic unsaturation; the term "alkylgroup" denotes a saturated hydrocarbyl group, whether straight orbranched chain; the term "primary alkyl group" denotes an alkyl grouphaving its valence bond from a carbon bonded to at least two hydrogens;the term "acyl group" denotes a group consisting of the residue of ahydrocarbyl monocarboxylic acid formed by removal of the hydroxylportion of the carboxyl group; the term "oxyhydrocarbyl" denotes amonovalent saturated cyclic or acylic group consisting of carbon,hydrogen, and oxygen containing only one oxygen in the form of an etherlinkage and includes tetrahydropyranyloxy, and other alternateexpressions such as lower alkoxy and lower alkoxy-lower alkyl; and theterm "lower", as applied to any of the foregoing groups, denotes a grouphaving a carbon skeleton containing up to and including eight carbons,such as methyl, ethyl, butyl, tert.-butyl, hexyl, 2-ethylhexyl, vinyl,butenyl, hexenyl, ethinyl, ethylene, methylene, formyl, acetyl,2-phenylethyl, benzoyl, methoxymethyl, 1-methoxyethyl,tetrahydropyran-2-yl and the like. The phraseology "lower alkylenedioxy,the monothia, monoaza or dithia chalcogen thereof" is used to indicate aketalized oxo or thio moiety and comprehends moieties of the formula--OR₈ O--, --OR₈ S--, --OR₉ N-- or --SR₉ S-- wherein R₉ is loweralkylene. Exemplary moieties are 1,2-ethylenedioxy,2,2-dimethyl-1,3-propylenedioxy, 1,2-ethylenedimercapto,2,3-butylenedioxy and the like. Phendioxy denotes a dihydroxy aryl groupsuch as catechol formed by removal of the hydrogen atoms from bothhydroxyl groups. By the terms alkoxy and alkoxy-lower alkyl are meantalkyl and alkyloxy-lower alkyl groups such as methoxy, ethoxy,tertiary-butoxy, 1-methoxy-ethyl, 2-ethoxy-ethyl and the like. Thephraseology "lower aralkyl" denotes groups such as benzyl,1-phenylethyl, 4-phenylbutyl and the like. The term "lower alkylaryl"comprehends ethylphenyl, o-tolyl and the like. Halogen denotes allhalogens, e.g., chlorine, fluorine, iodine and bromine.

In the formulae presented herein, the various substituents on cycliccompounds are joined to the cyclic nucleus by one of three notations, asolid line (--) indicating a substituent which is in the β-orientation(i.e., above the plane of the paper), a dotted line (----------)indicating a substituent which is in the α-orientation (below the planeof the paper), or a wavy line ( )

indicating a substituent which may be in either the α-or β-orientation.The formulae represented in Reaction Schemes C, D, D' and E indicate thecompounds in their racemic form except for the substituent defined by R₁which has been arbitrarily indicated as having the β-orientation.However, it will be appreciated that the synthesis described hereinuniquely lends itself to the preparation of each of the compoundsrepresented in the above-mentioned reaction schemes in its opticallyactive form, in which case the indicated absolute configuration at C₁₃(steroid numbering) is that of naturally occuring steroids. The R and Sdesignation of absolute stereochemistry employed herein is fullydescribed in R. S. Cahn at al., Experientia 12, 81 (1956).

In one aspect, this invention relates to the novel starting materials ofthe formulae II-a and II-b, intermediates therefor and their method ofpreparation schematically represented by Reaction Schemes A and B.

Illustrative examples of the substituted isoxazoles of formulae II-a andII-b include: 9-(3,5-dimethyl-4-isoxazolyl)-7-hydroxy-1-nonen-3-one;9-(3-methyl-4-isoxazolyl)-7-hydroxy-1-nonen-3-one;9-(3,5-diethyl-4-isoxazolyl)-7-hydroxy-1-nonen-3-one;9-(5-ethyl-4-isoxazolyl)-7-hydroxy-1-nonen-3-one;9-(3-methyl-5-phenyl-4-isoxazolyl)-7-hydroxy-1-nonen-3-one;2-(2-diethylaminoethyl)-6-[2-(3,5-dimethyl-4-isoxazolyl)ethyl]-tetrahydropyran-2-ol;2-(2-dimethylaminoethyl)-6-[2-(3-ethyl-4-isoxazolyl)ethyl]-tetrahydropyran-2-oland the like.

Other novel intermediates prepared in Reaction Scheme B are of theformula: ##SPC8##

wherein R₁₈ when taken alone is hydrogen; (R₁₉) n when taken alone islower alkoxy, lower acyloxy or hydroxy; and R₁₈ and (R₁₉) n when takentogether are carbonyl; U and U' are independently a single or a doublebond; R₁₅ and R₁₀ are defined as aforesaid; n is an integer having avalue of from 0 to 1 and is 0 when U' is a double bond.

Subgeneric to the compounds of formula XVI are novel compounds of theformula: ##SPC9##

wherein R₁₅, R₁₆, and R₁₀ are defined as aforesaid.

The 9-(3,5-disubstituted-4-isoxazolyl)-7-hydroxy-1-nonen-3-ones offormula II-a and2-(2-hydrocarbylaminoethyl)-6-[2-(3,5-disubstituted-4-isoxazolyl)ethyl]-tetrahydropyran-2-olsof formulae II-b can be obtained in accordance with Reaction Schemes Aand B via a Wittig-type reaction of acrolein dimer and a novel compoundof the formula ##SPC10##

wherein R'₁, R'₂, R'₃ R₁₅ and R₁₆ are defined as aforesaid.

Preferred compounds of formula D are those wherein R'₁, R'₂ and R'₃ areeach phenyl.

Substituted hydroxy isoxazole compounds of formula A of Reaction SchemeA can be conveniently obtained by means known in the art from thecorresponding 3,5-disubstituted-4-carboxy-isoxazoles. [Cf., G. Stork etal., J. Am. Chem. Soc. 89, 5461 (1967)].

The alcohols of formula A are converted to the compounds of formula B,in accordance with Step (1) of Reaction Scheme A. Suitably, the anionrepresented by X' is an inorganic anion derived from a mineral acide.g., chloride, bromide, iodide, sulfate or the like. A preferred anionis chloride in which case the compounds of formula B can be obtained bythe reaction of the alcohols of formula A with, for example, thionylchloride in methylene chloride solvent at a temperature of approximately-10°C. to +30°C.

The phosphonium salts of formula C can be obtained in accordance withStep (2) of Reaction Scheme A by treatment of the halide B with thedesired phosphine reagent such as, for example, triethylphosphine,triphenylphosphine, bis-(diethyl)-phenylphosphine and the like in asuitable solvent preferably a hydrocarbon, e.g., benzene, toluene or thelike at the reflux temperature of the solvent. The reaction ispreferably conducted under a nitrogen atmosphere.

The ylids of formula D can be generated from the compounds of formula Cin accordance with Step (3) of Reaction Scheme A by treatment of thecompounds of the formula C with an acid binding agent such as forexample, with an alkali metal-lower alkoxide, for example, sodiummethoxide; an alkali metal hydroxide such as sodium hydroxide; or analkali metal hydride such as sodium hydride in a suitable solvent,preferably dimethylsulfoxide. [Cf. R. Greenwald et al., J. Org. Chem.28, 1128 (1963)].

The thus obtained Wittig reagent of formula D can be employed to preparethe vinyl pyran compounds of formula F as schematically represented inReaction Scheme B by reacting the compounds of formula D with acroleindimer. The reaction is suitably conducted at a temperature between roomtemperature and 150°C. It has been found that a preferable temperaturerange in which to conduct the reaction is between 65° and about 75°. Thequantity of reactants used is not critical and an excess of either canbe used. However, it has been found advantageous to use an essentiallyequimolar ratio of reactants. This reaction is suitably effected in asolvent such as, for example, ethers, e.g., lower alkyl ethers such asdioxane and tetrahydrofuran; aromatic hydrocarbons such as benzene andxylene; di-lower alkyl-lower alkanoylamides such as dimethylformamideand dimethylacetamide; and dimethylsulfoxide. A preferred solvent forthis reaction is dimethylsulfoxide. Alternatively, the phosphonium saltsof formula C can be reacted directly with acrolein dimer by generatingin situ the ylid of formula D by adding the acid binding agent to thereaction system.

Conversion of the Wittig adduct of formula F to the heptanoic acidlactones of formula L can be accomplished via three separate reactionschemes as exemplified in Reaction Scheme B.

Thus, one method for preparing the lactones of formula L in accordancewith Steps (10), (11) and (12) of Reaction Scheme B comprises hydratingthe vinyl pyrans of formula F to the hemiacetals of formula O inaccordance with Step (10). The hydration is suitably effected at roomtemperature in an inert organic solvent such as tetrahydrofuran,dioxane, or a di-lower alkyl ketone such as acetone by means of amineral acid, preferably hydrochloric acid or sulfuric acid. Thehemiacetals of formula O can be converted to the vinyl lactones offormula P in accordance with process step (11 ) by oxidizing with asuitable oxidizing agent, preferably manganese dioxide in a hydrocarbonsolvent, preferably benzene at room temperature.

The heptanoic acid lactones of formula L are obtained in accordance withStep (12) of Reaction Scheme B by selective hydrogenation of theheptenoic acid lactones of formula P. A significant aspect of theinstant synthesis lies in the selective hydrogenation of olefinicallyunsaturated compounds containing an isoxazole moiety, e.g., Step (12) ofReaction Scheme B, without substantially attacking the isoxazole group.It is essential that this hydrogenation reaction be conducted so as toavoid any significant hydrogenation of the isoxazole moiety. Thehydrogenation is thus suitably conducted in the presence of a noblemetal catalyst, such as palladium, platinum, rhodium, etc. under mildreaction conditions, viz, without the addition of heat and substantiallyat atmospheric pressure. The noble metal catalyst can be utilized withor without a carrier and if a carrier is used, conventional carriers aresuitable. It is preferred to use a catalyst comprising palladium on acarbon carrier. The ratio of catalyst to substrate is not critical andcan be varied. However, it has been found advantageous to use a weightratio of catalyst to substrate from about 1:5 to about 1:100. Especiallypreferred is a ratio of 1:25. The hydrogenation is suitable effected inthe presence of an inert organic solvent, optionally in the presence ofacids or mono, di or trialkyl amines. Suitable solvents which may beemployed are ethers, such as diethylether or tetrahydrofuran; loweralkyl esters of lower alkanoic acids such as ethyl acetate; and aromatichydrocarbons such as toluene or benzene and the like. It is especiallypreferred to conduct the hydrogenation using an ethyl acetate solvent.

Alternatively, lactones of the formula L may be prepared from the vinylpyrans of formula F as exemplified in Reaction Scheme B by firstpreparing the hemiacetals of formula I via process Steps (2), (3) and(4). Thus, in accordance with Step (2), the vinyl pyran isoxazoles offormula F are converted to the acetals of formula G by an alcoholaddition process. The conversion is suitably effected using a mineralacid, preferably sulfuric acid, in the presence of a lower alcohol,preferably ethanol, which serves both as a solvent and a source for thealkoxy protecting group.

The hemiacetals of formula I can be prepared from the acetals of formulaG in accordance with process steps (3) and (4) by first selectivelyhydrogenating the acetals of formula G employing similar hydrogenatingconditions to that which were used to effect the hydrogenation of thecompounds of formula P to the compounds of formula L as described aboveand subsequently removing the alkoxy protecting group by means ofaqueous mineral acid, preferably sulfuric acid in an inert organicsolvent, preferably an ether such as dioxane and tetrahydrofuran, or adi-lower alkyl ketone such as acetone. This latter reaction can beconveniently carried out at room temperature.

The lactones of formula L can be obtained from the hemiacetals offormula I via Step (14) or alternatively via the sequential Steps (5),(6) and (7) of Reaction Scheme B. Thus, the 6-hydroxy tetrahydropyranylisoxazoles of formula I can be converted in accordance with Step (14) tothe lactones of formula L if mild oxidation conditions are employed. Theoxidation is suitably effected with an oxidizing agent such as manganesedioxide, nickel dioxide or the like. The reaction can be carried out inan inert organic solvent such as benzene, xylene or methylene chlorideat room temperature.

Alternatively, in accordance with Steps (5), (6) and (7) of ReactionScheme B, the lactones of formula L are prepared by first oxidizing thehemiacetals of formula I to the keto acids of formula J [Step (5)] usinga strong agent, preferably Jones reagent (chromium trioxide and aqueoussulfuric acid) in the presence of an organic solvent such as lower alkylketones, e.g., acetone or methylethyl ketone. Selective reduction of theketo acids of formula J in accordance with Step (6) of Reaction Scheme Busing a reducing agent such as sodium borohydride or lithium aluminumtri-tertiarybutoxy hydride in a suitable solvent such as, for example,ethers, e.g., tetrahydrofuran or dioxane or lower alkanols, e.g.,methanol, ethanol or isopropanol, yields the hydroxy acids of formula Kwhich on heating, preferably under reduced pressure, afford the lactonesof formula L in accordance with Step (7) of Reaction Scheme B.

In accordance with Step (8) of Reaction Scheme B, the lactones offormula L can be converted to the substituted hydroxy-non-1-en-3-ones offormula II-a by a novel reaction with a vinyl magnesium halide.Preferred halides are chloride, bromide and iodide. The reaction isconducted in the presence of an inert organic solvent, preferably anetheric reaction medium such as diethylether, diisopropylether,tetrahydrofuran, dioxane and the like. Surprisingly, it has been foundthat when the reaction is conducted under cold temperature conditions,the carbonyl group of the thus obtained vinyl-hydroxy compound offormula II-a is stable to further reaction with Grignard reagent. Thus,the reaction is suitably effected at a temperature of from -90°C. to0°C. and preferably at a temperature of from about -70°C. to about-60°C. The order of addition of the reactants is not critical althoughit is generally preferred to add the vinyl magnesium halide to thepyran.

Alternatively, the hydroxy-non-1-en-3-ones of formula II-a can beobtained from the lactols of formula I via Steps (17) and (18) ofReaction Scheme B. Thus, the dihydroxy compounds of formula N areobtained by reacting the lactols of formula L with vinyl magnesiumhalide. The conditions employed for this reaction are not critical tothis invention and are those normally employed in Grignard reactions.The reaction is normally conducted in the presence of an ethericreaction medium, such as diethylether, tetrahydrofuran and the like. Thereaction is normally effected at a temperature of from about 0° to about50°C.

In accordance with Step (18) of Reaction Scheme B, the 3-hydroxyl groupof the dihydroxy compounds of formula N is selectively oxidized in knownmanner using manganese dioxide to yield the nonenones of formula L.

Because of the susceptibility of the vinyl group of the7-hydroxy-1-nonen-3-ones of formula II-a to oxidation, it is desirablealthough not essential that these compounds be converted to more stablevariants.

Thus, it is preferred to utilize the compounds of formulae II-a in thevariant form of the hemiketals of the formula: ##SPC11##

wherein R₁₇, R₁₅ and R₁₆ are defined as aforesaid.

The internally hydrated Mannich base variants of formula II-b can beconveniently prepared without purification of the vinyl ketones II-a.The reaction sequence in accordance with Step (9) comprises adding tothe crude vinyl ketone solution obtained in accordance with Step (8)above, a mono-hydrocarbylamine or di-hydrocarbylamine, to yield theMannich base of formula II-b which is conveniently recovered from thesolution by solvent removal. The compound may be readily purified byextraction into dilute acid.

Alternatively, the 7-hydroxy-1-alken-3-one compounds of the formula II-acan be converted to another stable variant of the formula: ##SPC12##

wherein R₁₅ and R₁₆ are defined as aforesaid and R₁₈ is chloro,hydroxyl, lower alkoxy, mono- hydrocarbylamino, di-hydrocarbylamino andacid salts of these amines.

Exemplary of the amines which may be employed to form the compoundsrepresented by formulas II-b and II-a-1 are diethyl amine,methylbutylamine, butylamine, ethylbutylamine, cyclohexylamine,α-naphthylamine, diphenylamine, N-phenyl-2-naphthylamine or the like.Preferred are aliphatic primary or secondary lower hydrocarbyl amines,especially saturated lower hydrocarbyl secondary amines. Also preferredare the optically active amines described hereinafter.

The compounds of formula II-a-1 are readily produced from the vinylketones of formula II-a by known techniques, for example,1-chloro-7-hydroxy-alkan-3-ones are obtained by the Markownikoffreaction of the vinyl compound with hydrogen chloride in a known manner.1-Hydroxy and 1-alkoxy derivatives are obtained by the base catalyzedreaction of water or a lower alkanol, for example, methanol with thevinyl ketone. Additional derivatives are formed by the reaction of thevinyl ketone with a mono-hydrocarbyl amine or di- hydrocarbylamine asdescribed above. In some instances, it may be desirable to convert theMannich base to its crystalline acid addition salts. The acid salts ofthe amines of formula II-a-1 and similarly the hemiketals of formulaII-b are conveniently obtained by reacting the amines with the desiredanhydrous mineral or organic acid in a suitable aprotic solvent such asan ether or hydrocarbon. Preferred acids are hydrogen halides,especially hydrogen chloride and lower alkyl dicarboxylic acids,especially oxalic acid.

As is apparent, those compounds of formula II-a-1 wherein R₁₈ is mono-hydrocarbylamino, di-hydrocarbyl amino or acid salts of the amines andthe compounds of formula II-b are isomers. These isomers exist in theketone form of formula II-a-1 or in the cyclic hemiketal of formula II-bor as the equilibrium mixture of the two forms. Whether a particularMannich base of formula II-a-1 exists in that form or the hemiketal formor in an equilibrium mixture consisting primarily of one or the otherwill depend upon the environmental conditions in which it is placed,such as temperature, solvent and pH of reaction medium, as well as theparticular meaning of R₁₈ and R₁₇. Either form is useful for thepurposes of this invention since these isomers are used in a reactionwith compounds of formula III, infra, and either the acyclic forms offormulae II-a and II-a-1 or the cyclic hemiketal form of formula II-b isuseful for this purpose. A particular advantage of the cyclic form isits greater stability as compared with the acyclic form and also ascompared with the vinyl ketones of formula II-a-1. Acidic conditionsshift the equilibrium away from the cyclic form.

The starting materials of the formulae II-a, II-a-1 and II-b can eitherbe used in racemic form or in the optically active form. When used in anoptically active form the 7Rantipode is required to give naturallyoccurring steroids.

The optically active forms of the formulae II-a, II-a-1 and II-b can beconveniently obtained by several routes. For example, by the use of anoptically active amine such as α-phenethylamine, abietylamine ormenthylamine, one can resolve these compounds via salt formation. Thus,by reaction with a lower alkyl dicarboxylic acid, e.g., oxalic acid or ahydrogen halide acid, e.g., hydrogen chloride, suitable salts can beformed. An optically pure antipode of formulae II-a-1 or II-b is thusobtained after separation of the salts, with optional conversion of thesalts to the free amines by known means, e.g. by reaction with an alkalimetal hydroxide. These compounds are then used in the remainder of thereaction sequence of this invention.

Alternatively, the optically active antipodes of formulae II-a-1, II-aand II-b can be prepared, in a manner analogous to that employed toobtain the racemic materials, from the optically active lactones offormula L. These lactones are prepared by the sequence of Steps (15),(16) and (7) of Reaction Scheme B. Thus, racemic lactones L areconverted to the diastereomeric hydroxy esters or amides (Step 15) byreaction with an optically active alcohol, e.g., menthol, or anoptically active amine, e.g., α-phenethylamine in a neutral solvent,preferably benzene, toluene or xylene and preferably at the reflux pointof the solvents. The diastereomers of formula M are separated bycrystallization or preparative gas phase chromatography. Opticallyactive compounds of formula M are converted (Step 16) by treatment withan alkali metal hydroxide in alcohol or alcohol-water mixtures to theoptically active hydroxy acids of formula K. A preferred reagent issodium hydroxide in aqueous lower alcohol, preferably methanol atreflux. The optically active hydroxy acids of formula K are converted tothe optically active lactones of formula L (Step 7) exactly as describedpreviously for the racemic compounds, e.g., by thermal lactonization.

In still another method, the racemic lactones of formula L can behydrolyzed to the corresponding hydroxy acids of formula K which canthen be resolved by treatment with an optically active base, e.g.,brucine, ephedrine or quinine and separating the thus obtaineddiastereomeric salts.

Still other methods will be apparent to those skilled in the art.Resolution can also be effected at a latter stage in the synthesis aswill be more fully described hereinafter. The optically pure isomers offormulae II-a, II-a-1 and II-b are then used in the remainder of thereaction sequence of this invention and when coupled with the uniqueasymmetric induction and preservation of optical specificity thereofoffer a facile route to optically pure steroidal materials.

In a further aspect, this invention is concerned with the compounds offormulae I-a, I-b, I-c, X and XI and their method of preparation via thegeneral reaction scheme set forth in Reaction Scheme C.

Thus, in this aspect, this invention is concerned with novelcyclopenta[f][l]benzopyrans having the tricyclic nucleus ##SPC13##

and novel naphtho 2,1-b pyrans having the tricyclic nucleus ##SPC14##

These novel compounds are generally defined by the formula: ##SPC15##

wherein Y, Z, R₁, R₁₅ and R₁₆ are defined as aforesaid; T representseither a single or a double bond; U represents a single or a double bondand is a single bond when T is a single bond; m is an integer having avalue of from 1 to 2; n is an integer having a value of from 0 to 1 andis 0 when T represents a double bond and is 1 when T represents a singlebond; r is an integer having a value of from 0 to 1 and is 0 when T is adouble bond and 1 when T is a single bond; and s is an integer having avalue of from 0 to 1 and is 0 when U is a double bond and 1 when U is asingle bond.

Preferred compounds are those wherein Y is defined so that R₁₅ and R₁₆are both lower alkyl especially wherein both R₁₅ and R₁₆ are methyl --i.e., 3,5-dimethyl-4-isoxazolylmethylene; R₁ is n-alkyl, especiallymethyl and ethyl; and, when s has a value of 1, the 9α-(when m is 1) or10α- (when m is 2) hydrogen is trans-oriented with respect to R₁.

Subgeneric to the tricyclic compounds of formula I are the3-substituted-6αβ-alkyl-1,2,3,5,6,6a,7,8-octahydrocyclopenta-[f][l]benzopyransand the3-substituted-6αβ-1,2,5,6,6a,7-8,9-octahydro-3H-naphtho[2,1-b]pyrans,hereinafter referred to as "dienes" having the formula: ##SPC16##

wherein R₁, Z, Y and m are as defined above, the 3-substituted-6aβ-alkyl-1,2,3,5,6,6a,7,8,9,9a-decahydrocyclopenta[f][l] benzopyrans andthe 3-substituted-6aβ-alkyl-1,2,5,6,6a,7,8,9,10,10a-decahydro-3H-naphtho[2,1-b]pyranshereinafter referred to as "monoenes" represented by the formula:##SPC17##

wherein R₁, Z, Y and m are as defined above; and the 3-substituted-6aβ-alkyl-4a-hydroxyperhydrocyclopenta-[f][l]benzopyrans and the3-substituted-6aβ-alkyl-4a-hydroxyperhydro-3H-naphtho[2,1-b]pyrans andtheir lower alkyl ethers and monoacyl esters; hereinafter referred to as"perhydro" compounds, represented by the formula: ##SPC18##

wherein R₁, R₂, Z, Y and m are as defined above.

The second reactant employed in the condensation in accordance with Step(a) of Reaction Scheme C as generally mentioned above is a 2-(loweralkyl)cycloalkane-1,3-dione of the formula: ##SPC19##

wherein R₁, Z and m are as defined above. These compounds are knowncompounds and description of their synthesis is accordingly unnecessary.Suitable compounds include 2-methylcyclopentane-1,3-dione;2-ethylcyclopentane-1,3-dione; 2-propylcyclopentane-1,3-dione;2-butylcyclopentane-1,3-dione; 2-methylcyclohexane-1,3-dione;2-ethylcyclohexane-1,3-dione and the like.

Thus, the process of this invention comprises in this aspect inaccordance with Reaction Scheme C the general steps of (a) condensationof a 7-hydroxy-1-alken-3-one (II-a) or a variant thereof (II-a-1; II-b)with a 2-alkylcycloalkane-1,3-dione (III) to produce diene (I-a); (b)saturation of the 9,9a-or 10,10a-double bond of diene (Ia) to producemonoene (Ib); (c) introduction of a hydroxy, alkoxy, or acyloxy group atthe 4a-position and a hydrogen atom at the 9b- or 10b-position ofmonoene (Ib) to produce perhydro (Ic); (d) oxidation of the perhydrocompound of formula (Ic) to form the bicyclic compound of formula X and(e) cyclization of the bicyclic compound to produce benz[e]indenecompounds of formula XI.

The conditions for the condensation of ketone (II-a) or variant (II-a-1or II-b) with cyclic dione (III) are not narrowly critical, although itis preferred, particularly when the acyclic ketone is charged as thevinyl ketone, that a nonoxidizing atmosphere, e.g., nitrogen or argon,be employed. If desired, an antioxidant, for example, phenolic compoundssuch as hydroquinone may be employed. Furthermore, the reaction can beconducted in the absence or presence of acid or base promoters. Suitablebasic promoters include those heretofore known to promote the Michaelcondensation, including inorganic bases, for example, alkali metalhydroxides, such as sodium hydroxide or potassium hydroxide and organicbases, including alkali metal alkoxides, for example, sodium orpotassium methoxide or ethoxide, and ammonium hydroxides, particularlybenzyltrialkylammonium hydroxides. A preferred class of base promotersare the amines, especially tertiary amines and most preferablypyridine-type compounds such as pyridine and the picolines. Acidpromoters which can be employed include organic carboxylic acids such asacetic acid or benzoic acid; organic sulfonic acids such asp-toluenesulfonic acid; and mineral acids such as sulfuric acid,phosphoric acid, hydrochloric acid and the like. The amount of promoteremployed is not narrowly critical and can vary from catalytic amounts tomolar amounts.

The ratio of ketone (II-a) or variant (II-a-1 or II-b) to 2-loweralkyl-cycoalkane-1,3-dione (III) is not narrowly critical althoughapproximately equimolar amounts are preferred. Although there is noparticular advantage to the use of excesses of either reactant, the2-alkyl-cycloalkane-1,3-dione can be more readily employed in excessbecause, due to its general low solubility in known organic solvents,unreacted cycloalkanedione can be easily recovered from the reactionmixture.

The reaction temperature is not critical and can vary from roomtemperature or below to reflux temperature or higher. The condensationis preferably conducted in the presence of an inert solvent to insure afluid reaction mixture and uniform reaction temperatures. Primaryalcohols are not desirable due to their tendency to react with vinylketones. Suitable solvents include tertiary alcohols such astert.-butanol; aliphatic and aromatic hydrocarbons such as cyclohexane,hexane, octane, benzene, xylene, toluene and the like; ethers such asdiethylether, tetrahydrofuran and the like; chlorinated hydrocarbonssuch as carbon tetrachloride, chloroform and the like; as well asdipolar aprotic solvents such as dimethylsulfoxide and theN,N-disubstituted amides such as dimethylformamide or dimethylacetamide.

The product of the condensation, depending upon the nature of thereaction promoter employed, can be one or both of the compounds havingthe formulae: ##SPC20##

wherein R₁, Y and m are as defined above.

When the promoter is an acid or a relatively weak base, such aspyridine, or when no promoter is employed at all, the reaction productobtained is the diene, i.e., the tricyclic enol ether (I-a-1). When astrong base, such as sodium or potassium hydroxide, is employed as apromoter, a crystalline product having the formula VI is isolated.However, the compounds of formula VI upon treatment with an acid, suchas acetic acid, para-toluenesulfonic acid, or sulfuric acid, readilyform the dione, i.e., tricyclic enol ether (I-a-1).

The dienes of formula I-a in the presence of water and acid, e.g.,sulfuric acid in acetone, aqueous acetic acid or aqueous hydrochloricacid in dioxane, undergo acid hydrolysis to form indenones of theformula: ##SPC21##

wherein R₁, Y and m have the same meaning as above.

The indenones of formula I-a' are themselves convertible to compounds offormula I-a via dehydration, for example, via acid catalyzed azeotropicdistillation in benzene. Suitable acid catalysts are p-toluenesulfonicacid, potassium bisulfate, boron trifluoride etherate and the like. Thisreversible hydrolysis of compounds of formula I-a is useful in theirpreparation and purification. Thus, in instances where the directpurification of compounds of formula I-a is difficult it is often morefacile to hydrolyze the compound of formula I-a to a compound of formulaI-a', which can then be purified, for example, by chromatography, andsubsequently be reconverted to the desired compound of formula I-a viadehydration.

The condensation of a vinyl ketone of formula II-a or a variant thereofof formulae II-a-1 or II-b with a cycloalkane-1,3-dione of formula IIIresults in a specific stereochemical induction at one member of thecritical C/D-ring junction. Thus, this invention is particularlyadvantageous in that it involves a unique asymmetric induction. Theproducts of the condensation, i.e., the dienones of formula I-a, have atleast two asymmetric centers at positions-3 and -6a permittingtheoretically of two racemates or four optical antipodes. However, as aresult of the condensation described in this invention, when using aracemic starting material of formulae II-a, II-a-1 or II-b only a singleracemate of formula I-a results and when using an optically activestarting material of formulae II-a, II-a-1 or II-b, only a singleoptical antipode of formula I-a results. It has further been found thatwhen starting with a compound of formulae II-a, II-b or II-a-1 with a7R-configuration there is obtained the more desirable optical antipodeof formula I-a having a 6aβ-absolute configuration. Thus, to preparesteriodal materials having the more desired 13β-absolute configurationby the synthesis of this invention one can either start with the7R-antipode of formulae II-a, II-a-1 or II-b which can be prepared bythe methods described aforesaid or one can resolve at some intermediatestage subsequent to the condensation with a cycloalkanedione of formulaIII or one can resolve the end-product steriodal material. In any event,the unique asymmetric induction concurrent to the condensation of thisinvention renders the obtention of a single optical antipode as anend-product more facile.

The compounds of general formula I-a-1 as described above are readilyconverted to their corresponding derivatives of the formula: ##SPC22##

wherein Y, R₁, R₇, R₈ and m are as previously defined.

Thus, the ketodienes of formula I-a-1 are readily converted to thecorresponding 7β-alcohols and their esters or ethers as represented bythe formula I-a-2 above by the sequence of reactions comprisingreduction of the ketone to the alcohol and, if desired, subsequentesterification or etherification.

The reduction can be effected by any of several known methods for thechemical reduction of a ketone, e.g., by reaction of dienone (I-a-1)with a group III-metal reducing agent. Group III-metals include thosehaving atomic numbers of from 5 to 13, inclusive, i.e., boron andaluminum. Illustrative examples of these reducing agents includetri(lower alkoxy)aluminum compounds such as triisopropoxyaluminum;di(lower alkyl)aluminum hydrides such as diethylaluminum hydride anddiisobutylaluminum hydride; alkali metal-Group III-metal complexhydrides such as lithium aluminum hydride, sodium aluminum hydride, andsodium borohydride; tri(lower alkoxy)alkali metal-Group III-metalcomplex hydrides such as trimethoxy lithium aluminum hydride andtributoxy lithium aluminum hydride and the like. The alkali metal-GroupIII-metal complex hydrides are preferred as reducing agents, withlithium aluminum hydride being especially preferred.

This reaction is effected in any suitable inert reaction medium such ashydrocarbons, e.g., cyclohexane, benzene, toluene and xylene or ethers,e.g., diethylether, diisopropylether and tetrahydrofuran. Proticsolvents such as water or alcohols should not be employed when lithiumaluminum hydride is the reducing agent, but can be employed with sodiumborohydride.

The remaining reaction conditions are not narrowly critical, although itis generally preferred to effect the reduction at reduced temperatures,i.e., below room temperature (about 20°-25°C.). Temperatures in therange of from about 0°C. to about room temperature are normallyemployed.

The free alcohol is recovered from the reaction mixture after treatmentof the mixture with acid. The alcohol can be esterified in known manner,for example, by base-catalyzed reaction with a carboxylic acid halide orcarboxylic acid anhydride. Illustrative bases include inorganic basessuch as sodium hydroxide and potassium hydroxide and organic bases suchas a sodium alkoxide or an amine, especially a tertiary amine, and moreparticularly, pyridine and the picolines. Similarly, the alcohols can bereacted in a known manner to yield the ethers of formula I-a-2.

The ketodienes of formula I-a-1 can also be converted to their7β-hydroxy-7α-hydrocarbyl derivatives represented by the formula I-a-2above by reaction with a Grignard reagent of the formula:

    R.sub.8 MgT                                                VII

wherein R₈ is as previously defined and T is a halogen having an atomicnumber of from 17 to 35 inclusive (i.e., chlorine or bromine).

This Grignard reaction is conducted in a known manner. For example, theGrignard reagent is prepared by reacting a hydrocarbyl halide withmagnesium in an ether reaction medium, for example, ethylether ortetrahydrofuran at elevated temperature, generally in the range of fromabout 30°C. to about 75°C. The ketodiene compound I-a-1) is then addedto the Grignard solution at about room temperature, although higher orlower temperatures can be employed. The resulting reaction product ishydrolyzed to produce the free alcohol, which can be esterified oretherified as discussed above.

The second step of the general synthesis of the tricyclic compounds ofthis invention comprises conversion of the dienes of formula I-a to themonoenes of formula I-b in accordance with Reaction Scheme C by aselective catalytic hydrogenation. The hydrogenation must be conductedunder mild process conditions so as to avoid hydrogenating the isoxazolemoiety. Suitable noble metal catalysts are palladium, platinum andrhodium with the preferred catalyst being palladium. These catalysts canbe employed in the form of the metal alone, or can be deposited onsuitable support materials, such as carbon, alumina, calcium carbonate,barium sulfate and the like. The hydrogenation is preferably conductedin the presence of inert solvents such as hydrocarbons, alcohols, ethersand the like. The reaction conditions of pressure and temperature arecritical. Thus, the hydrogenation is effected at a pressure of about oneatmosphere and a temperature of about room temperature. These ambientconditions are generally preferred to avoid significant hydrogenation ofthe 4a,9b(10b)-double bond or the isoxazole moiety. The hydrogenationmedium can be acidic or neutral as may be desired, although a neutralmedia, such as hydrocarbons, e.g., toluene or hexane is preferred forbest results. Optionally, the reaction medium can include mono, di ortri-alkyl amines. In general, hydrogenation of the diene of formula I-aleads to the corresponding monoene of formula I-b.

Via the aforesaid catalytic hydrogenation, monoenes of formula I-bhaving a C/D-trans ring junction are formed in a major proportion whenhydrogenating a diene of formula I-a-2. This method thus provides anadvantageous synthesis of C/D-trans steroidal materials. Whenhydrogenating a diene of formula I-a-1, C/D-cis compounds are formed ina major proportion. This method thus provides an advantageous synthesisof C/D-sis steroidal materials. However, when the dienes areintermediates for the synthesis of steroids having theC/D-trans-orientation, this technique of using the free carbonylderivative is not particularly desirable. When monoenes of formula I-bhaving C/D-trans configuration are desired, it is preferable to firstreduce the dienone of formula I-a-1 to a corresponding hydroxy compoundof formula I-a-2 as described aforesaid prior to the catalytichydrogenation. Following the catalytic hydrogenation, the cabonyl moietyin formula I-b-1 can be regenerated by conventional means, such asoxidation with chromium trioxide, if desired.

The monoenes of formula I-b prepared by the above-describedhydrogenation contain at least three asymmetric centers, at positions-3, -6a and -9a when m is one and at positions -3, -6a and -10a when mis two. With respect to these three centers, there are thus eightantipodal configurations possible. By virtue of the unique asymmetricinduction described in this invention, proceeding from a racemicstarting material of formulae II-a, II-a-1 or II-b, only four of theseantipodes of formula I-b are prepared and proceeding from an opticallyactive starting material of formulae II-a-1, II-a or II-b, only two ofthese antipodes of formula I-b are prepared. Moreover, by theabove-described hydrogenation, there can predominantly be prepared oneantipode, having the desired 6a,9a(10)-trans-ring juncture. Thus, theeventual obtention of the more desired 13β-C/D-trans-configuration inthe ultimate steroidal products is rendered more facile by thestereoselective reactions provided by this invention.

The monoenes of formula I-b are converted to the perhydro compounds offormula I-c by reacting the monoene with a compound having the formula:

    R.sub.2 OH                                                 VIII

wherein R₂ is as previously defined.

That is, the monoene of formula I-b is reacted with water, a primaryalcohol, or a carboxylic acid. This reaction is catalyzed by mineral ororganic acids, for example, hydrochloric acid, phosphoric acid, sulfuricacid, para-toluenesulfonic acid, and the like. Sulfuric acid is thepreferred acid catalyst and water the preferred reactant. Although notnecessary, it is desirable to conduct this reaction in the presence ofan added solvent, particularly in the event the compound of formula VIIIis water. In this case, it is desirable to employ a solvent which isboth miscible with water and a solvent for the monoene of formula I-b.Solvents of this nature include acetone, tert.-butanol, dioxane and thelike. The reaction temperature is not critical and ambient temperatureis normally employed, although higher and lower temperatures could beemployed if desired.

It should be noted that the perhydro compounds of formula I-c can alsoexist in equilibrium with an open isomeric form of the formula Ic-1##SPC23##

wherein R₁, R₂, Z, m and Y are as defined aforesaid.

Under the process conditions employed in the instant synthesis thecyclic form of the formula I-c predominates in the equilibrium mixture.

The compound of formula I-c is oxidized to form the bicyclic compound ofthe formula X in accordance with Step (d) of Reaction Scheme C bycontact with an oxidizing agent such as chromic acid, potassiumdichromate, or potassium permanganate. Jones reagent (chromium trioxideand aqueous sulfuric acid with acetone as solvent), or a chromicacid-acetic acid mixture is preferred as oxidizing agent. The nature ofZ is unchanged in this reaction, except when Z is hydroxymethylene [--CH(OH)--]. In this instance, unless the hydroxyl group is protected,as by formation of a lower acyl ester, it is oxidized to form a carbonylgroup. Further, if Z is a ketal, if may be cleaved to form the freecarbonyl group. The reaction temperature is not narrowly critical andtemperatures in the range of from 0°C. to about 75°C. are suitable,although ambient temperature is preferred.

The bicyclic compound (X) is treated with acid or base to effectcyclization to the tricyclic compound of formula (XI) in accordance withStep (e) of Reaction Scheme C. In this reaction, it is preferred thatthe water of reaction be removed when acidic conditions are employed asby refluxing the reaction mixture with an azeotroping agent andseparating the water from the condensate. Suitable strong acids aresulfuric acid, p-toluenesulfonic acid, potassium bisulfate and the like.Alternatively, base catalyzed dehydration can be utilized, for example,by refluxing compound (X) in the presence of methanolic sodiumhydroxide. It should be noted that when starting with a C/D-trans enolether of the formula I-b, a trans-anti configuration will be obtained inthe enone of the formula XI, i.e, the C₈ hydrogen (Steroid numbering)will be beta.

Alternatively, compounds of the formula XI-b ##SPC24## can be preparedfrom 1,2,3,3a,4,5,8,9,9a,9b-decahydro-3aβ-alkyl-7-oxo-7H-benz[e]indenesand 4,4a,4b,5,6,7,8,8a,9,10-decahydro-8aβ-alkyl-3H-phenanthren-2-oneswherein the 6 and 1 positions respectively are substituted withhydrogen, by alkylation with a 4-halomethyl isoxazole. The reaction issuitably conducted in an organic solvent such as 1,2-dimethoxyethane,dimethylsulfoxide, or a lower alcohol, e.g., ethanol in the presence ofa strong base such as an alkali metal alkoxide, e.g., sodium methoxideor an alkali metal hydride, e.g., sodium hydride. The reaction can beconducted at a temperature range of from room temperature to the refluxtemperature of the solvent.

A further aspect of this invention relates to the process andintermediate compounds employed to convert the benz[e]indenes andphenanthren-2-ones of formula XI-a in accordance with Reaction Scheme Dto 19-nor-steroids of the formula XIV-a.

The cycloolefin compounds of formula XI-a are hydrogenated to thetricyclic compounds of formula XV in accordance with Step (f) ofReaction Scheme D. The hydrogenation is preferably effected in a loweralcohol solvent, e.g., ethanol using a palladium metal catalyst andcarbon carrier although other noble metal catalysts may be employed. Thehydrogenation is conducted under neutral, acidic or weakly basicconditions substantially at atmospheric pressure and room temperature soas to selectively hydrogenate the Δ⁹(10) -bond without substantiallyhydrogenating the isoxazolyl moiety. Suitable weak bases for thispurpose are mono, di or tri-lower alkyl amines, preferably triethylamine. It has been found that the use of base in this hydrogenation stepaides in selectively promoting the formation of the compound of formulaXV which has a trans-anti-trans configuration when trans-anti enones offormula XI-a are employed as reactants.

Use of aqueous hydrobromic acid, e.g., 0.003-10 mole equivalents of HBrwith a 0.1-20 percent Pd/BaSO₄ catalyst in a lower alkanol, e.g.,methanol or ethanol, in this hydrogenation step results in the promotionof the selective formation of the compounds of formula XV which have atrans-anti-cis configuration when the trans-anti-enones of formula XI-aare employed. In this reaction pressures of preferably about 1 atm. anda temperature of about room temperature may be conveniently employed.

The conversion of the tricyclic compounds of formula XV to the steroidsof formula XIV-a can be accomplished by three alternative reactionmethods. Thus, process routes (1), (m), (o) and (K') hereinafterreferred to as the "heterocyclic anhydrous basic route" and (1), (m'),(o') and (k') hereinafter referred to as "heterocyclic aqueous basicroute" exemplified in Reaction Scheme D can be employed. The thirdmethod is described in Reaction Scheme D'.

At this point in the process, it should be noted that all hydrogenationsconducted thus far viz, Steps (3) and (12) of Reaction Scheme B, Step(b) of Reaction Scheme C and Step (f) of Reaction Scheme D have beencarefully conducted under mild hydrogenating conditions, i.e., in theabsence of strong base and substantially at room temperature andatmospheric pressure to selectively avoid hydrogenating the isoxazolemoiety to any significant degree. However, the isoxazole group can nowbe readily cleaved as described hereinafter.

The tricyclic compounds of formula XV can be converted to the19-nor-steroids of formula XIV-a via the "heterocyclic anhydrous basicroute" which comprises sequential process Steps (1), (m), (o) and (k')of Reaction Scheme D. Thus, the vinylogous amides of formula XXVII canbe obtained from the tricyclic compounds of formula XV via Step (1), inthe same reaction mixture that was employed to hydrogenate the compoundsof formula XI-a to the compounds of formula XV[Step (f)], by theaddition of strong base to the reaction medium and then furtherhydrogenating. Alternatively, hydrogenation of the isoxazole group ofthe isolated compound XV can be suitable conducted in the presence of acatalyst, preferably, a noble metal catalyst, such as rhodium,palladium, platinum, and the like or Raney nickel. The catalyst can beutilized with or without a carrier and if a carrier is used,conventional carriers are suitable. Especially preferred is 10 per centPd/C. The ratio of catalyst to substrate is not critical and can bevaried. However, it has been found advantageous to use a weight ratio ofcatalyst to substrate from about 1:5 to about 1:25. Especially preferredis a ratio of 1:10. The hydrogenation is suitably effected in an organicsolvent, preferably a lower alcohol at room temperature and atmosphericpressure in the presence of strong base, although higher temperaturesand pressure may be employed. Preferred bases for the secondhydrogenation are strong alkali metal hydroxides, e.g., potassiumhydroxide, sodium hydroxide and the like. Treatment of the vinylogousamides of formula XXVII with anhydrous base, in accordance with Step (m)of Reaction Scheme D, results in dehydration and acyl cleavage of thecompounds of formula XXVII to yield the dihydro pyridines of formulaXXVIII. Preferred anhydrous bases for this conversion are alkali metallower alkoxides, especially sodium ethoxide. The reaction isconveniently carried out in a lower alcohol solvent, preferably ethanol.Hydrolysis of the substituted dihydropyridines of formula XXVIII withaqueous alcoholic base in accordance with Step (o) of Reaction Scheme Dyields the diketone compounds of formula XIII'. Cyclization of thelatter compounds, which are not isolable, occurs rapidly to give19-nor-steroids of formula XIV-a in accordance with Step (k') ofReaction Scheme D.

It should be noted when employing the anhydrous basic route tha the acylgroup ##STR5## is selectively cleaved, thus enabling use of mixedisoxazoles, e.g., those wherein R₁₅ and R₁₆ are not identical. Thisroute thus permits obtention of uniform steroidal products vis. -- thosesubstituted at the steroidal C-4 position solely with an R'₁₅substituent.

19-Nor-steroids of formula XIV-a can alternatively be obtained from thevinylogous amides of formula XXVII via sequential process steps (m'),(o') and (k') - viz., the heterocyclic aqueous basic route. The mostsignificant difference between the heterocyclic aqueous basic route andthe heterocyclic anhydrous basic route described immediately aforesaid,lies in the difference between process Steps (m) and (m'). In the formercase, strong anhydrous base is employed in Step (m) yieldingheterocyclic compounds of formula XXVIII and in the latter case strongaqueous base such as, for example, aqueous metal hydroxides, preferablyNaOH, is employed in Step (m' ) yielding triketones of formula XXLX. Itshould be noted, however, that the aqueous basic route is not selectiveand probably also proceeds via Step (m) as well as Step (m' ). Thediketones of formula XIII', which are obtained in accordance with Step(o') by cleaving the triketones of formula XXIX, further react bycyclizing (Step K') to yield steroids of formula XIV-a. The acylcleavage effected in accordance with Step (o') is not selective, that isto say it is not possible to predict whether the ##STR6## group or the##STR7## acyl group will be cleaved. It is, therefore, desirable whenemploying the aqueous basic route that R₁₅ and R₁₆ be identical oreither R₁₅ or R₁₆ be hydrogen in order to avoid the obtention of mixedsteroidal products. If either R₁₅ or R₁₆ is hydrogen, selective cleavageof the formyl group occurs, thus avoiding mixed steroidal products.

It should be emphasized as one further facet of the stereoselectivity ofthe instant invention, that when tricyclic compounds of formula XVhaving a trans-anti-trans-configuration are employed in Reaction SchemeD, steroids of formula XIV-a having atrans-anti-trans-anti-configuration are produced. This is highlydesirable since many pharmacologically valuable compounds possess thisconfiguration.

Furthermore, when tricyclic compounds of formula XV having atrans-anti-cis configuration are used in Reaction Scheme D, steroids offormula XIV-a having a trans-anti-cis-anti-configuration are produced.These compounds are 19-nor-9β,10α-steroids which are also known as19-nor-retrosteroids and form a further class of pharmacologicallyvaluable compounds.

In compounds represented by the formulae XXVII, XXVIII and XIII' ofReaction Scheme D, Z' is defined in an identical manner to Z as definedaforesaid, with the proviso that Z' can not be a loweralkylenedioxy-methylene, phendioxy-methylene or dialkoxymethylene orester function. However, the end-products of formula XIV-a substitutedin the 17-position (steroidal numbering) by Z are obtained from theprecursors of the formulas which are substituted in the 17-position byZ' by means known in the art.

When effecting the conversion of benz[e]indenes and phenanthren-2-onesof formula XI-a to the steroids of formula XIV-a via either theheterocyclic aqueous basic group or the heterocyclic anhydrous basicgroup in accordance with Reaction Scheme D, variable amounts ofpyridines are produced even when oxygen is excluded from the reactionmedium. These pyridine products presumable arise from oxidation ordisproportionation of some of the intermediates.

Therefore, another aspect of this invention relates to the process andintermediate compounds employed to convert the tricyclic compounds offormula XV to the steroids of formula XIV-a in accordance with ReactionScheme D' via process Steps (g), (h), (i), (j) and (k) which avoids theformation of pyridine intermediates and thereby correspondingly raisesthe yield of steroids produced. Pyridine formation is avoided inaccordance with teachings of this invention by preventing cyclization tothe vinylogous amides of formula XXVII (Reaction Scheme D) by firstprotecting the 7-position of the tricyclic compounds of formula XV priorto hydrogenating the isoxazole moiety.

The protected compounds of formula XXV are obtained from the tricycliccompounds of formula XV in accordance with Step (g) of Reaction SchemeD' by converting the free oxo group of the compounds of formula XV to agroup represented by Z" as defined aforesaid. This protection can beeffected by ketalization to form the phendioxy-methylene, loweralkylenedioxy-methylene, dilower alkoxy-methylene, or the monothia,monoaza, or dithia chalcogen thereof by means known in the art.Preferred ketals are 1,2-ethylenedioxy, 2,3-butylenedioxy, and2,2-dimethyl-1,3-propylenedioxy which can be obtained by reaction of thecompounds of formula XV with the corresponding alcohols in a knownmanner. Alternatively, the oxo moiety can be converted to its dithiaketal by reaction with dithioethane in a known manner, for example, inacetic acid at room temperature and in the presence of borontrifluoride. Moreover, a monothia ketal can similarly be prepared in aknown manner, for example, by reaction of the oxo moiety with2-mercaptoethanol in dioxane at room temperature in the presence of zincchloride and sodium sulfate. Also, the monoaza ketals can be prepared ina known manner, for example, by reaction of the oxo moiety with2-hydroxyethylamine in the presence of acid.

Further, the oxo moiety can be reduced to the corresponding hydroxycompound with for example, sodium borohydride at low temperature and canthen be etherified or esterified. A preferred ether protecting group istertiarybutoxy which can conveniently be obtained from the correspondinghydroxy derivative by reaction under acid conditions with isobutylene bymeans known in the art.

The oxo moiety can be regenerated from its protected form at any desiredstage of the reaction sequence. Thus, it can be readily produced byhydrolysis of the alkylenedioxy ketals in a known manner. Similarly, itcan be regenerated from the dithia ketal in a known manner, for example,by treatment with phenylmercuric chloride and calcium carbonate inethanol or by treatment with methanolic hydrochloric acid. Also, it canbe regenerated from a monothia ketal in a known manner, for example, bytreatment under strongly acidic conditions, for example, by treatmentwith aqueous sulfuric acid in dioxane or hydrochloric acid in aceticacid. Moreover, it can be regenerated from a monoaza ketal in a knownmanner, for example, by treatment with a strong aqueous acid. Also,ethers and/or esters can be reconverted to the free hydroxy group whichin turn can be oxidized to give the oxo moiety.

The protected compounds of formula XXV are hydrogenated in accordancewith Step (h) of Reaction Scheme D' to yield the vinylogous amides offormula XXVI. The hydrogenation is conducted under process conditionssuitable to hydrogenate the isoxazolyl groups. A catalyst, preferably anoble metal catalyst, such as platinum, palladium and the like or Raneynickel or the like is employed. Especially preferred is the palladiumcatalyst. The nobel metal catalyst can be utilized with or without acarrier and if a carrier is used, conventional carriers are suitable. Itis preferred to use palladium on carbon. Especially preferred is 10percent Pd/C. The ratio of catalyst to substrate is not critical and canbe varied. However, it has been found advantageous to use a weight ratioof catalyst to substrate from about 1:5 to 1:25. Especially preferred isa ratio of 1:10. The hydrogenation is suitably effected in the presenceof strong base, preferably an alkali metal hydroxide, e.g., potassiumhydroxide in an inert organic solvent for example, lower alcohols, e.g.,methanol, ethanol or isopropanol. The reaction conditions of pressureand temperature are not narrowly critical as is the case when it isdesired to avoid hydrogenating the isoxazole moiety. Therefore, ifdesired, pressures above one atmosphere and temperatures above roomtemperature may be suitably employed.

The vinylogous amides of formula XXVI are hydrolyzed to the diketones offormula XXX in accordance with Step (i) and cleaved in accordance withStep (j) of Reaction Scheme D' to yield the ketones of formula XIIIusing aqueous alkali hydroxide, preferably sodium hydroxide. The acylcleavage effected in accordance with Step (j) is not selective. It isnot possible to predict whether the ##STR8## group or the ##STR9## acylgroup will be cleaved. It is, therefore, desirable when employing thisroute that R₁₅ and R₁₆ be selected so as to be identical or in thealternative either R₁₅ or R₁₆ be hydrogen to avoid the obtention ofmixed steroid products. It should be noted, that if the function atposition C-17 (steroid numbering) is an ester, it will be cleaved to thefree alcohol under the conditions employed in Steps (i) and (j).

Treatment of the ketone of formula XIII wherein Z" is a ketal functionwith a mineral acid, preferably hydrochloric acid in a lower alcoholsolvent, suitably methanol at reflux, yields the steroids of formulaXIV-a via Step (k) of Reaction Scheme D' by a process sequence ofremoval of the protecting group and cyclization. For cases wherein theprotecting group Z" of the ketone of formula XIII is other than a ketalfunction, the group is first removed and the free carbonyl group isregenerated by known methods, e.g., in the case of an alcohol with anoxidizing agent such as Jones reagent, prior to cyclization (Step k).

It should be noted that the process steps carried out in Reaction SchemeD' are stereoselective viz -- if the tricyclic compounds of formula XVhave a trans-anti-trans-configuration the steroid products of formulaXIV-a have a trans-anti-trans-anti-configuration while if the tricycliccompounds of formula XV have a trans-anti-cis configuration the steroidproducts of formula XIV-a have a trans-anti-cis-anti-configuration.

In compounds represented by formulae XXV, XXVI and XIII of ReactionScheme D, Z" is defined in an identical manner to Z, as definedaforesaid, with a proviso that Z" can not be a a free carbonyl function.However, the end products of formula XIV-a substituted in the17-position by Z are obtained from the precursors of formula XIV-a whichare substituted in the 17-position by Z" by means known in the art.

Still another aspect of this invention relates to the process andintermediate compounds employed to convert the benz[e]indenes andphenanthren-2-ones of the formula XI-a in accordance with ReactionScheme E to the estrones of the formula XXXVI.

The enones of formula XI-a are converted to the protected Δ⁹(11)-compounds of formula XXXI in accordance with Step (a) of ReactionScheme E, wherein R₁, R₁₅, R₁₆, Z, Z", W, V and m are defined asaforesaid. Protection can be effected by ketalization of the freecarbonyl group of the compound of the formula XI-a via methodspreviously described (Step g, Reaction Scheme D'). Preferred ketals are1,2-ethylenedioxy, 2,3-butylenedioxy, 2,2-dimethyl-1,3-propylenedioxyand the like. As is evident from the structure of compounds of formulaeXI-a and XXXI ketalization results in isomerizing the Δ⁹(10)-unsaturated compounds to the Δ⁹(11) -unsaturated compounds.

The protected compounds of formula XXXI are hydrogenated in accordancewith Step (b) to yield the Δ⁹(11) -vinylogous amides of formula XXXII.The hydrogenation is conducted under identical conditions employed forthe hydrogenation in accordance with Step (h) of Reaction Scheme D.Unexpectedly, it has been found in accordance with the teachings of thisinvention that the hydrogenation of the compound of formula XXXI isselective, that is only the isoxazole moiety is hydrogenated withouthydrogenating the Δ⁹(11) -unsaturated bond to any significant degree.

The resulting vinylogous amide of formula XXXII is treated as before,e.g., Steps (i) and (j) of Reaction Scheme D' with aqueous alkali metalhydroxide base to yield the Δ⁹(11) -ketones of formula XXXIII. TheΔ⁹(10) -diketones of formula XXXIV are obtained from the Δ⁹(11) -ketonesof formula XXXIII in accordance with Step (d) of Reaction Scheme E bytreatment with aqueous mineral or organic acid, preferably acetic acidat a temperature range of 50°C. to the reflux temperature of thesolvent.

The diketo Δ⁹(10) -compounds of formula XXXIV can be converted to the Δ⁴, Δ⁹(10) -steroids of formula XXXV. In a specific embodiment, the dieneof formula XXXV, wherein Z is carbonyl, R'₁₅ is hydrogen, R₁ is methyland m is 1 can be isomerized to the pharmaceutically valuable compoundof formula XXXVI (estrone) via Step (f) of Reaction Scheme E if thetrans-anti-stereoisomer of formula XI-a is used as a starting reactant.These methods of Steps (e) and (f) are more fully described in FrenchPat. No. 1,305,092, Assignee Roussel-Uclaf.

The compound of formula XIV-a, Reaction Scheme D', wherein Z iscarbonyl, m is 1, R₁ is ethyl and R'₁₅ is hydrogen(19-nor-18-homo-androst-4-ene-3,17-dione), can be selectivelyalkynylated by a suitable organo metallic acetylide affording norgestrel(13β-ethyl-17α-ethinyl-17-hydroxy-gon-4-ene-3-one), a knownprogestational agent. Exemplary of the suitable alkynylating agents toeffect the conversion to norgestrel are the alkali acetylides such aslithium acetylide, potassium acetylide, sodium acetylide and the like.The reaction is carried out in the presence of liquid ammonia in asuitable solvent system such as benzene or toluene. The alkynylation iseffected preferably at the reflux temperature of the reaction mediumalthough temperatures from -60°C. to 30°C. are suitable. Exemplary ofother suitable reagents to effect the acetylenic addition is lithiumacetylide diamine complex in dimethylformamide as solvent.

Compounds of formula XIV-a wherein Z is carbonyl can be converted intocorresponding pharmaceutically valuable known pregnane compounds i.e.,compounds of which Z is of the formula: ##STR10## by known procedures.(Cf., U.S. Pat. No. 3,383,385, Bucourt et al.). These procedures forconverting androstan-17-ones into pregnanes are best effected if allcarbonyl groups other than that at C-17 are initially protected. Thus,for example, 19-nor-14β-androst-4-ene-3,17-dione can be converted into19-nor-14β-17α-progesterone.

The 19-nor-compound of formula XIV-a, Reaction Scheme D', wherein m is1, R₄ is propyl and R'₁₅ is hydrogen are ovulatory inhibitors [cf.,Tetrahedron Letters, 127 (1967), Velluz et al.]. Additionally, compoundsof formula XIV-a wherein R₁ is methyl, R'₁₅ is hydrogen, m is 1 and Z iscarbonyl have been converted to 19-nor-testosterone acetate, J. Org.Chem., 26, 3904 (1961), L. J. Chinn et al.

Compounds of formula XIV-a of Reaction Scheme D' having thetrans-anti-cis-anti configuration have been described in the literature.Thus racemic 19-nor-9β, 10α-androst-4-en-3,17 -dione (Z is carbonyl, mis 1, R'₁₅ is hydrogen and R₁ is methyl) is disclosed by Torgov et al.,Chemistry of Natural Compounds, 1, 138 (1965). Optically active19-nor-9β,10α-testosterone (Z is hydroxymethylene, m is 1, R'₁₅ ishydrogen and R₁ is methyl) was described by Velluz et al., ComptesRendues, 252, 3903 (1961) while the 17α-methyl derivative of thiscompound is described by Farkas et al., J. Org. Chem, 34 3022 (1969).

As has been pointed out above, the products of this invention areproduced in the form of various optically active antipodes, which can becarried through the entire reaction sequence, or which can be resolvedat suitable places during the reaction sequence. For example, at anystage wherein a compound having a secondary hydroxyl group is present,one can react the secondary alcohol with a dicarboxylic acid to form ahalf ester. Suitable dicarboxylic acids include lower alkyl dicarboxylicacids such as oxalic acid, malonic acid, succinic acid, glutamic acid,adipic acid, or aromatic carboxylic acids such as phthalic acid. Theresulting half-ester is then reacted with an optically active base, suchas brucine, ephedrine, or quinine, to produce a diastereomeric salt. Thesalts, after separation, are then readily reconverted to opticallyactive alcohols. As an alternative, the secondary alcohol can be reactedwith an optically active acid, for example, camphorsulfonic acid. Theresulting diastereomeric esters are then separated and reconverted tothe alcohols.

It is preferred that the resolution be effected at some stage in thesynthesis of the compounds of formulae II-a, II-a-1 or II-b as by theresolutions heretofore described. Resolution at such early stages in theoverall process described herein is highly preferred because of theimproved efficiency in the production of steroids having a desiredconfiguration. Because the condensation of the alken-3-one or variant(II-a-1, II-a or II-b) with cycloalkanedione (III) is stereo-specific,as are the subsequent reaction steps, one, by proper selection ofstereoisomers at these early stages, can ensure that substantially allof the tricyclic compounds of this invention and the steroids derivedtherefrom have a selected configuration. Thus, by this technique, theproduction of compounds of the undesired configuration is minimized orprevented entirely, with an attendant increase in the efficiency of theproduction of compounds of the desired configuration.

A further aspect of the present invention relates to novel19-nor-retrosteroids of the formula ##SPC25##

where R is lower alkyl with at least 2 carbon atoms.

Compounds of formula XXXVI are anabolic, androgenic agents with afavorable anabolic/androgenic ratio. They are pituitary inhibitors,anti-estrogenic and lower cholesterol level in blood.

In the claims, all compounds should be construed to include,independently, the racemic form of the compound and independently eachenantiomeric form unless specifically indicated otherwise.

The following examples are illustrative but not limitative of theinvention. All temperatures are stated in degrees centigrade. Infrared,ultraviolet and nuclear magnetic resonance spectra where taken wereconsistent with exemplified structures.

EXAMPLE 1 Preparation of 4-carboethoxy-3,5-dimethylisoxazole

A solution of 320 ml. (325 g. = 2.5 moles) of ethyl acetoacetate, 209ml. (178 g. = 2.5 moles) of pyrrolidine and 600 ml. of reagent gradebenzene was heated at reflux with azeotropic removal of water for twohours. The benzene was then removed at reduced pressure and the residuewas distilled through a 10-cm. Vigreux column yielding 427 g. of ethylβ-pyrrolidineocrotonate as a light yellow liquid, b.p. 155°-156°/10 mm.

A solution of the ethyl β-pyrrolidinocrotonate (427 g. = 2.33 moles),190 ml. (182 g., 2.43 mole) of nitroethane and 1300 ml. of triethylaminein 1200 ml. of anhydrous chloroform was cooled in an ice bath undernitrogen. A solution of 235 ml. (393 g. = 2.56 mole) of phosphorousoxychloride in 400 ml. of chloroform was added at such a rate that thetemperature did not rise above 15°. During the addition, which tookplace over a three-hour period, a viscous orange precipitate formed.This suspension was then stirred under nitrogen overnight. As muchsolvent as possible was removed at reduced pressure and the resultingred-brown paste was diluted with water and extracted with ether. Theether solutions were washed sequentially with water, 3N hydrochloricacid, water, 5 percent sodium hydroxide solution and water, and weredried over anhydrous sodium sulfate. Solvent removal at reduced pressuregave a dark oil which was distilled through a short Vigreux column togive 4-carboethoxy-3,5-dimethyl-isoxazole as a slightly cloudy,colorless liquid of b.p. 100°/11mm.

EXAMPLE 2 Preparation of 3,5-dimethyl-4-hydroxymethylisoxazole

A suspension of 100 g (2.63 moles) of lithium aluminum hydride in 2.5liters of anhydrous ether was stirred under nitrogen as a solution of272 g. (1.61 mole) of the 4-carboethoxy-3,5-dimethylisoxazole preparedin Example 1 above in 400 ml. of anhydrous ether was added at such arate as to maintain a gentle reflux. The suspension was stirred at roomtemperature under nitrogen overnight, during which time an extremelygummy green-gray mass formed in the bottom of the flask. The mixture wascooled in an ice bath and hydrolyzed with saturated aqueous sodiumsulfate solution. Anhydrous sodium sulfate was added to dry the ethersolution. The salts were removed by filtration and washed carefully withether and chloroform. Solvent removal from the filtrates, finally at50°/0.1 mm., gave a white crystalline mass. This was triturated with hotether and then cooled. Filtration gave3,5-dimethyl-4-hydroxymethyl-isoxazole as white prisms, m.p.76.5°/77.5°. Concentration of the mother liquors gave a second crop ofprisms, m.p. 76.5°-78°.

EXAMPLE 3 Preparation of 4-chloromethyl-3,5-dimethylisoxazole

A solution at 36.3 ml. (60.0 g., 0.5 mole) of thionyl chloride in 50 ml.of methylene chloride was cooled in an ice bath under a very slightnegative pressure (for fume removal). A solution of 40.0 g. (0.314 mole)of 3,5-dimethyl-4-hydroxymethylisoxazole in 75 ml. of methylene chloridewas added over 2 1/2 hours. The resulting solution was stirred at roomtemperature for 2.0 hours. The solvent was removed at reduced pressureand the residue was distilled to give the desired chloride as a paleyellow liquid, b.p. 91.5°-93°/15 mm.

EXAMPLE 4 Preparation of(3,5-dimethyl-4-isoxazolylmethyl)triphenylphosphonium chloride

A solution of 59.6 g. (0.402 mole) of4-chloromethyl-3,5-dimethylisoxazole, prepared as described above, and116 g. (0.44 mole) of triphenylphosphine in 1 liter of toluene washeated at reflux under nitrogen for 6 hours. The resulting suspensionwas cooled and filtered. The filtrate was heated at reflux for anadditional 20 hours. The precipitate was again removed by filtration andthe combined solids were washed well with ether and benzene. The solventwas removed from the filtrate and the residue was taken up in 150 ml. offresh toluene and refluxed for an additional 18 hours. Filtration asbefore gave another small quantity of solid. The combined solids werecrystallized from ethanol-ether to give the desired phsophonium salt asa cream-white solid, m.p. 313°-316°.

A sample from a similar preparation was crystallized again fromethanol-ether to give analytically pure material as small white prisms,m.p. 303°-305°. (The melting point of this compound is dependent on therate of heating.)

Anal. Calcd. for C₂₄ H₂₃ ClNOP: C, 70.67; H, 5.68; Cl, 8.69; N, 3.44; O,3.92; P, 7.60. Found: C, 70.73; H, 5.69; N, 3.55; Cl, 8.66.

EXAMPLE 5 Preparation of racemic3,5-dimethyl-4-(3,4-dihydro-2H-pyran-2-ylvinyl) isoxazole

8.75 G. (0.20 mole) of 55 percent sodium hydride dispersion was washedunder nitrogen with dry pentane to remove the mineral oil. To the flaskwas added 600 ml. of dimethylsulfoxide (dried over Linde 3A molecularsieves). The resulting suspension was carefully degassed, placed undernitrogen, and heated at 70°-75° for 1 hour. The gray-green solution wascooled to approximately 15° and 91.6 g. (0.20 mole) of(3,5-dimethyl-4-isoxazolylmethyl)triphenylphosphonium chloride, preparedas described in Example 4 above, was added in one portion. Afterapproximately 5 minutes, a bright orange precipitate formed in theinitially dark red solution. This suspension was stirred at roomtemperature for 45 minutes. To the mixture was then added, drop-wise viasyringe, 25.0 g. (0.223 mole) of acrolein dimer (freshly distilled fromand into hydroquinone) at such a rate that the temperature remained lessthan 30° (10-15 minutes with water bath cooling). The light orange-brownsolution was stirred at room temperature for 20 minutes, and then at60°-65° for 3 hours. (In some experiments, the mixture became very blackduring the heating period). The reaction mixture was cooled, poured ontoice, and slurried until all of the dark oil solidified. The suspensionwas filtered and the filter cake was washed well with pentane. Thefiltrates were extracted with pentane and the pentane solutions werewashed with water and brine and dried over anhydrous sodium sulfate.Solvent removal gave a slightly orange oil which was distilled from asmall quantity of anhydrous potassium carbonate to give the desiredproduct as a colorless liquid, b.p. 83°-85°/0.1 mm. A similarly preparedsample of b.p. 77°-80°/0.5 mm. was submitted for analysis.

Anal. Calcd. for C₁₂ H₁₅ NO₂ : C, 70.22; H, 7.37; N, 6.82; O, 15.59.Found: C, 70.45; H, 7.44; N, 6.60.

EXAMPLE 6 Preparation of racemic7-(3,5-dimethyl-4-isoxazolyl)-5-hydroxy-Δ⁶ -heptenoic acid lactone

To a solution of 33.5 g. (0.163 mole) of3,5-dimethyl-4-(3,4-dihydro-2H-pyran-2-ylvinyl) isoxazole, prepared asdescribed in Example 5 above, in 400 ml. of dioxane, was added 400 ml.of 1N sulfuric acid and the cloudy solution, which soon cleared, wasstirred at room temperature for 1 hour. The mixture was poured into 2liters of saturated aqueous sodium bicarbonate solution and extractedwell with ether. The ether extracts were washed with brine and driedover anhydrous sodium sulfate. Solvent removal gave a colorless oil, theinfrared spectrum of which indicated that complete hydration of the enolether had taken place. This material was taken up in 2 liters of benzeneand placed under nitrogen. To the flask was added 400 g. of manganesedioxide and the resulting suspension was stirred at room temperature for40 hours. The manganese dioxide was removed by filtration and carefullywashed with fresh benzene. Solvent removal from the filtrate gave 23 g.of yellow solid. Two crystallizations of this material frombenzene-ether gave the desired lactone as a cream-white powder, m.p.90.0°-91.5°. A sample from a similar preparation was crystallized againfrom the same solvent pair to give analytically pure material as finewhite needles, m.p. 91°-92.5°.

Anal. Calcd. for C₁₂ H₁₅ NO₃ : C, 65.14; H, 6,83; O, 21.70; N, 6.33.Found: C, 64.93; H, 6.71; N, 6.06.

EXAMPLE 7 Preparation of racemic7-(3,5-dimethyl-4-isoxazolyl)-5-hydroxyheptanoic acid lactone

A. From racemic 7-(3,5-dimethyl-4-isoxazolyl)-5-hydroxy-Δ⁶ -heptenoicacid lactone

A mixture of 16.80 g. (76.0 mmoles) of racemic7-(3,5-dimethyl-4-isoxazolyl)-5-hydroxy- Δ⁶ -heptenoic acid lactone, 400ml. of ethyl acetate, and 500 mg. of 10 percent palladium on carbon washydrogenated at room temperature and atmospheric pressure. Uptake (1.25× theoretical) was rapid and ceased after 2 hours. The catalyst wasremoved by filtration and washed with fresh ethyl acetate. Solventremoval gave a colorless oil which was crystallized from ether at -20°to give the desired product as white microprisms, m.p. 59°-62°. A smallportion of a similarly prepared sample was crystallized again from etherto give white microprisms of m.p. 61°-62.5°, λ_(max) ^(ethanol) 220 mμ(ε = 5350).

Anal. Calcd. for C₁₂ H₁₇ NO₃ : C, 64.55; H, 7.68; O, 21.50; N, 6.27.Found: C, 64.59; H, 7.77; N, 6.12.

B. From 3,5-dimethyl-4-(3,4-dihydro-2H-pyran-2-ylvinyl) isoxazole

To a solution of 1.0 g. (4.88 mmoles) of3,5-dimethyl-4-(3,4-dihydro-2H-pyran-2-ylvinyl) isoxazole, prepared asdescribed in Example 5 above, in 10 ml. of ethanol was added 5 drops of1N sulfuric acid. The solution was stirred at room temperatureovernight, poured into excess saturated aqueous sodium bicarbonatesolution, and extracted with ether. The ether extracts were washed withwater and saturated brine and dried over anhydrous sodium sulfate.Solvent removal gave 1.25 g. of pale yellow liquid whose infraredspectrum indicated that formation of racemic3,5-dimethyl-4-(6-ethoxytetrahydropyran-2-ylvinyl)isoxazole wascomplete. This material was taken up in 10 ml. of ethyl acetate. To thissolution was added 25 mg. of 10 percent palladium on carbon and theresulting mixture was hydrogenated at room temperature and atmosphericpressure. After 2 hr., one equivalent of hydrogen had been consumed anduptake ceased. The catalyst was removed by filtration and washed withfresh ethyl acetate. Solvent removal from the filtrates gave 1.28 g. ofracemic 3,5-dimethyl-4-(6-ethoxytetrahydropyran-2-ylethyl)-isoxazole asa colorless oil whose infrared spectrum indicated that the hydrogenationwas complete. This crude acetal was taken up in 20 ml. of dioxane. Tothe flask was added 10 ml. of 1N sulfuric acid and the resultingsolution was stirred at room temperature for 4 hr. It was then pouredinto excess saturated aqueous sodium bicarbonate solution and extractedwith ether. The ether extracts were washed with saturated brine anddried over anhydrous sodium sulfate. Solvent removal gave racemic3,5-dimethyl-4-(6-hydroxytetrahydropyran-2-ylethyl)-isoxazole as aviscous oil. The crude hemiketal was taken up in 25 ml. of1,2-dichloroethane, degassed and placed under nitrogen. To the flask wasadded 7.5 g. of manganese dioxide and the resulting suspension wasstirred at room temperature overnight. The manganese dioxide was removedby filtration and washed with fresh solvent. Solvent removal from thefiltrates gave a pale yellow resin which was crystallized from ether at-20°C. to give the desired acetone as a white solid of m.p. 60°-62°. Asimilarly prepared sample was shown by its infrared and nmr spectra,mixture melting point, and thin layer chromatographic behavior to beidentical with the material prepared as described above in part A.

C. Via Racemic 7-(3,5-dimethyl-4-isoxazolyl)-5-oxo-heptanoic acid

A solution of3,5-dimethyl-4-(6-hydroxytetrahydropyran-2-ylethyl)-isoxazole, preparedas described in part B from 60.5 g. (0.294 mole) of racemic3,5-dimethyl-4-(3,4-dihydro-2H-pyran-2-ylvinyl)-isoxazole, in 600 ml. ofacetone was cooled in an ice bath as 400 ml. of Jones reagent was addeddropwise over a 1.0 hr. period. The resulting suspension was stirred atroom temperature overnight. Saturated sodium bisulfite solution wasadded to destroy the excess oxidizing agent and most of the acetone wasremoved at reduced pressure. The residue was diluted with water,saturated with sodium chloride, and extracted with ethyl acetate. Theethyl acetate solutions were washed with brine and then with excesssaturated aqueous sodium bicarbonate solution. The sodium bicarbonatesolutions were washed with ether, acidified with 3N hydrochloric acid,saturated with sodium chloride, and extracted with ethyl acetate. Theethyl acetate solutions were washed with brine and dried over anhydroussodium sulfate. Solvent removal at reduced pressure gave a pale yellowresin. Crystallization of this material from ether gave two crops ofracemic 7-(3,5-dimethyl-4 -isoxazolyl)-5-oxo-heptanoic acid as a finewhite powder, m.p. 61.5°-63.5°.

Anal. Calcd. for C₁₂ H₁₇ NO₄ : C, 60.24; H, 7.16; N, 5.85. Found: C,60.15; H, 7.29; N, 5.78.

A solution of the keto acid prepared above (41.2 g., 0.173 mole) in 600ml. of isopropyl alcohol was placed under nitrogen. To this solution wascarefully added 10.0 g. (0.296 mole) of sodium borohydride. After theinitial vigorous reaction had subsided, the cloudy solution was heatedat reflux overnight. A major portion of the solvent was then removed atreduced pressure. The residue was diluted with water, acidified with 1Nhydrochloric acid, saturated with salt, and extracted with ether. Theether solutions were washed with brine and dried over anhydrous sodiumsulfate. Solvent removal at reduced pressure gave racemic7-(3,5-dimethyl-4-isoxazolyl)-5-hydroxyheptanoic acid as a cloudycolorless resin. This material was heated to 220°/0.3 mm., at which timea colorless liquid rapidly distilled. Crystallization from ether gavethe desired lactone as white prisms, m.p. 61°-63°.

EXAMPLE 8Racemic-3-[2-(3,5-dimethyl-4-isoxazolyl)ethyl]-6aβ-methyl-1,2,3,5,6,6a-hexahydrocyclopenta[f][1]benzopyran-7(8H)-one

A. A solution of 10.0 g. (44.8 mmoles) of racemic7-(3,5-dimethyl-4-isoxazolyl)-5-hydroxyheptanoic acid lactone, preparedas described in Example 7 above, in 150 ml. of freshly distilledtetrahydrofuran was cooled in a dry ice-isopropyl alcohol bath undernitrogen. A 25 per cent (weight/volume) solution of vinyl magnesiumchloride in tetrahydrofuran (25 ml., 75 mmoles) was added via syringe ata rate such that the temperature remained at approximately -60°. Themixture was stirred at -70° for 15 min., and then carefully hydrolyzedwith 5 ml. of methanol. It was then poured onto ice, 24 g. of ammoniumchloride, and 8 ml. of acetic acid. The resulting solution was extractedwith ether and the ether solutions were washed with water, saturatedaqueous sodium bicarbonate solution, and saturated brine and dried overanhydrous sodium sulfate. After 10 minutes, 10 ml. of diethylamine wasadded to the ethereal solution of racemic9-(3,5-dimethyl-4-isoxazolyl)-7-hydroxynon-1-en-3-one. Ten minuteslater, solvent removal gave crude racemic2-(2-diethylaminoethyl)-6-[2-(3,5-dimethyl-4-isoxazolyl)ethyl]tetrahydropyran-2-olas a light yellow oil. This material was taken up in ether and extractedwith a total of 100 ml. of 1N hydrochloric acid followed by 25 ml. ofwater. The aqueous solutions were washed with ether and then placedunder a layer of ether in an ice bath. The solution was made basic with3N sodium hydroxide and then extracted with ether. The ether extractswere washed with water and saturated brine and dried over anhydroussodium sulfate. Solvent removal gave the Mannich base as a pale yellowoil.

A solution of 5.3 g. (47.2 mmoles) of 2-methylcyclopentane-1,3-dione in150 ml. of toluene and 50 ml. of acetic acid was carefully degassed,placed under nitrogen and heated at reflux for 5 minutes. A solution ofthe Mannich base prepared above in 50 ml. of toluene was added andrefluxing was continued for 2 hr. The cooled solution was washed withwater, saturated aqueous sodium bicarbonate solution and saturated brineand dried over anhydrous sodium sulfate. Solvent removal gave areddish-orange gum which was filtered through 150 g. of Woelm neutralalumina, activity grade III. Elution with benzene brought off a lightpink band followed by a yellow band. Solvent removal from the eluentgave the desired dienol ether as a light orange crystalline solid.

A sample of this product was crystallized from etherhexane and then fromether at -20° to give analytically pure racemic3-[2-(3,5-dimethyl-4-isoxazolyl)ethyl]-6aβ-methyl-1,2,3,5,6,6a-hexahydrocyclopenta[f][1]benzopyran-7(8H)-one as light yellow prisms of m.p. 113°-116°.

Anal. Calcd. for C₂₀ H₂₅ NO₃ : C, 73.36; H, 7.70; N, 4.28; O, 14.66.Found: C, 73.64; H, 7.72; N, 4.57.

B. To a solution of 20.0 g. (89.6 mmoles) of racemic7-(3,5-dimethyl-4-isoxazolyl)-5-hydroxy heptanoic acid lactone, preparedas described in Example 7 above, in 100 ml. of dry toluene, which hadbeen cooled to -70°C. under nitrogen, was added 95 ml. of a 20% solutionof diisobutylaluminum hydride dropwise over a period of 3/4 hour. Themixture was stirred 1 hour at -70°C., and then hydrolyzed in the coldwith 80 ml. of 6 N sulfuric acid. After the solution had warmed to roomtemperature, the layers were separated and the organic solutions werewashed with water, saturated aqueous sodium bicarbonate solution andbrine and dried over anhydrous sodium sulfate. Solvent removal atreduced pressure gave racemic3,5-dimethyl-4-(6-hydroxytetrahydropyran-2-ylethyl)isoxazole as 18.1 g.of colorless viscous oil.

In a previously dried flask, 200 ml. of a 1 M solution of vinylmagnesium chloride in tetrahydrofuran was stirred at room temperature asa solution of the hemiacetal prepared above (alternatively, hemiacetalprepared as described in Example 7 may be used) in 50 ml. oftetrahydrofuran was added at such a rate that the temperature remainedless than 35°. The mixture was stirred at room temperature overnight andthen hydrolyzed by pouring onto ice and ammonium chloride. Extractionwith ether, washing the ether solutions with brine, drying overanhydrous sodium sulfate, and solvent removal gave racemic9-(3,5-dimethyl-4-isoxazolyl)-non-1-en-3,7-diol as a viscous colorlessresin.

To a solution of the diol prepared above and 0.25 g. of hydroquinone in600 ml. of 1,2-dichloroethane was added 120 g. of manganese dioxide. Theresulting slurry was stirred 6 hours at room temperature before themanganese dioxide was removed by filtration. The filter cake was washedwell with fresh 1,2-dichloroethane and the combined filtrates wereconcentrated to 500 ml. To this solution of racemic9-(3,5-dimethyl-4-isoxazolyl)-7-hydroxy non-1-en-3-one was added 10 ml.of diethylamine. After 1/2 hour, solvent removal at reduced pressuregave crude racemic2-(2-diethylaminoethyl)-6-[2-(3,5-dimethyl-4-isoxazolyl)ethyl]tetrahydropyran-2-ol as a light yellow oil. This material was taken upin ether and extracted with a total of 100 ml. of 1N hydrochloric acidfollowed by 25 ml. of water. The aqueous solutions were washed withether and then placed under a layer of ether in an ice bath. Thesolution was made basic with 3N sodium hydroxide and then extracted withether. The ether extracts were washed with water and saturated brine anddried over anhydrous sodium sulfate. Solvent removal gave the Mannichbase as a pale yellow oil.

A solution of 5.3 g. (47.2 mmoles) of 2-methylcyclopentane-1,3-dione in150 ml. of toluene and 50 ml. of acetic acid was carefully degassed,placed under nitrogen and heated at reflux for 5 minutes. A solution ofthe Mannich base prepared above in 50 ml. of toluene was added andrefluxing was continued for 2 hours. The cooled solution was washed withwater, saturated aqueous sodium bicarbonate solution and saturated brineand dried over anhydrous sodium sulfate. Solvent removal gave areddish-orange gum which was filtered through 150 g. of Woelm neutralalumina, activity grade III. Elution with benzene gave dienol etherspectrally identical with the material prepared in part A as a paleorange solid.

EXAMPLE 9 Preparation of racemictrans-anti-6-[(3,5-dimethyl-4-isoxazolyl)methyl]-3a-methyl-1,2,3a,4,5,9,9a,9b-octahydro-3H-benz(e)indene-3,7(8H)-dione

A suspension of 1.60 g. (41 mmoles) of lithium aluminum hydride in 150ml. of freshly distilled tetrahydrofuran was cooled under nitrogen in anice bath as a solution of 12.0 g. of the dienol ether racemic3-[2-(3,5-dimethyl-4-isoxazolyl)ethyl]-6aβ-methyl-1,2,3,5,6,6a-hexahydrocyclopenta[f][1]benzopyran-7-(8H)-one, the preparation of which is described inExample 8, in 50 ml. of tetrahydroguran was added over 10 minutes. Thesuspension was stirred at 0° for another 10 minutes and then at roomtemperature for 1/2 hr. The mixture was cooled again in an ice bath,carefully hydrolyzed with saturated aqueous sodium sulfate solution, anddried over anhydrous sodium sulfate. The salts were removed byfiltration and washed with fresh tetrahydrofuran and chloroform. Solventremoval from the filtrates gave a cream-white solid. Normally thehydroxy dienol ether thus obtained was used without furtherpurification. However, the material from one experiment was crystallizedfrom ethertetrahydrofuran and then from tetrahydrofuran to giveanalytically pure racemic3-[2-(3,5-dimethyl-4-isoxazolyl)ethyl]-6aβ-methyl-1,2,3,5,6,6a,7,8-octahydrocyclopenta[f][1]benzopyran-7β-ol, as a cream-white crystalline powder, m.p.158.5°-165°.

Anal. Calcd. for C₂₀ H₂₇ NO₃ : C, 72.92; H, 8.26; O, 14.57; N, 4.25.Found: C, 73.22; H, 8.26; N, 4.03.

The crude hydroxy dienol ether prepared above was dissolved in 350 ml.of freshly distilled tetrahydrofuran. To this solution was added 750 mg.of a 5 per cent palladium on carbon catalyst and the resulting mixturewas hydrogenated at atmospheric pressure and room temperature. Uptake ofone equivalent of hydrogen took 4 hours. The catalyst was removed byfiltration and washed with fresh tetrahydrofuran. Solvent removal gaveracemictrans-3-[2-(3,5-dimethyl-4-isoxazolyl)ethyl]-6a-methyl-1,2,3,5,6,6a,7,8,9,9a-decahydrocyclopenta[f][1]benzopyran-7β-ol as a pale green resin.

A solution of the hydroxy enol ethertrans-3-[2-(3,5-dimethyl-4-isoxazolyl)ethyl]-6a-methyl-1,2,3,5,6,6a,7,8,9,9a-decahydrocyclopenta[f][ l] benzopyran-7β-ol prepared above in 250 ml. of acetone was stirredat room temperature with 125 ml. of 1N sulfuric acid for 11/2 hr.,during which time the solution became light pink in color. This solutionwas carefully poured into excess saturated aqueous sodium bicarbonatesolution and extracted with chloroform. The chloroform solutions werewashed with brine and dried over anhydrous sodium sulfate. Solventremoval gave racemictrans-3-[2-(3,5-dimethyl-4-isoxazolyl)ethyl]-6a-methyl-perhydrocyclopenta[f][ l] benzopyran-4a,7β-diol as a yellow resin. The infrared spectrum ofthis sample showed that complete hydration of the enol ether hadoccurred.

A solution of the hemiketaltrans-3-[2-(3,5-dimethyl-4-isoxazolyl)ethyl]-6a-methyl-perhydrocyclopenta[f][ l] benzopyran-4a,7β-diol in 400 ml. of acetone was cooled in an icebath as a solution of 20 g. (0.20 mole) of chromium trioxide in 100 ml.of 6N sulfuric acid was added dropwise over 1/2 hr. The mixture wasstirred at 0° for another 1/2 hr., and then at room temperature for 11/2hr. It was then diluted with water and extracted with benzene. Thebenzene extracts were washed with water, saturated aqueous sodiumbicarbonate solution and saturated brine and dried over anhydrous sodiumsulfate. Solvent removal gave racemictrans-4-[3-oxo-5(3,5-dimethyl-4-isoxazolyl)pentyl]-1a-methyl-perhydroindan-1,5-dioneas a pale yellow resin.

The crude trionetrans-4-[3-oxo-5-(3,5-dimethyl-4-isoxazolyl)pentyl]-1a-methyl-perhydroindan-1,5-dionewas dissolved in 100 ml. of methanol, carefully degassed and placedunder nitrogen. To the solution was added 1 g. of potassium hydroxideand the resulting black mixture was heated at reflux under nitrogen for11/2 hr. The cooled solution was diluted with water and extracted withbenzene. The benzene extracts were washed with water and saturated brineand dried over anhydrous sodium sulfate. Solvent removal gave 8.33 g. ofan orange solid which was filtered through 150 g. of Woelm neutralalumina, activity grade I. Elution with 3:1 benzene:ether slowly broughtoff the desired isoxazole ene-dione (In later experiments, the use ofactivity grade III neutral alumina and elution with benzene was found tobe superior). Crystallization from benzene-hexane gave the desiredproduct as white prisms, m.p. 141°-143.5°. A sample from a similarpreparation was crystallized again from benzene-hexane to give ananalytically pure material, m.p. 141.5°-143.5°.

Anal. Calcd. for C₂₀ H₂₅ NO₃ : C, 73.36; H, 7.70; N, 4.28; O, 14.66.Found: C, 73.39; H, 7.64; N, 4.38.

EXAMPLE 10 Preparation of racemic 19-nor-Androst-4-en-3,17-dione

A mixture of 1.00 g. (3.06 mmoles) of the isoxazole ene-dione racemictrans-anti-6-(3,5-dimethyl-4-isoxazolylmethyl)-3a-methyl-1,2,3a,4,5,9,9a,9b-octahydro-3H-benz(e)indene-3,7(8H)-dione,prepared as described in Example 9 above, 60 mg. of 10 per centpalladium on carbon, and 100 ml. of 3:1 ethanol triethylamine washydrogenated at atmospheric pressure and room temperature. Within 1hour, one equivalent of hydrogen had been taken up and uptake hadceased. Normally, the product was not isolated. In one case however, thecatalyst was removed by filtration and after solvent removal the crudeproduct was crystallized from benzene-hexane to give pure racemictrans-anti-trans-anti-6-[(3,5-dimethyl-4-isoxazolyl)methyl]-3a-methyl-3a,4,5,5a,8,9,9a,9b-octahydro-1H-benz[e]inden-3,7(2H,6H)-dioneas white prisms of m.p. 137.5°-139.5°.

Anal. Calcd. for C₂₀ H₂₇ NO₃ : C, 72.92; H, 8.26; N, 4.25; O, 14.57.Found: C, 72.89; H, 7.93; N, 4.22, 4.34.

To the hydrogenation mixture described above was added 10 ml. of a 1Npotassium hydroxide in ethanol solution which had been carefullydegassed and placed under nitrogen. After 11/2 hr., a second equivalentof hydrogen had been taken up. The catalyst was removed by filtrationand washed with fresh ethanol. Solvent removal from the filtrates gavethe vinylogous amide as a pale yellow resin which was immediately takenup in 25 ml. of butyl alcohol. This solution was carefully degassed andplaced under nitrogen. To the flask was added 100 ml. of a previouslydegassed 20 per cent aqueous potassium hydroxide solution. The resultingtwo phase mixture was heated at reflux under nitrogen for 20 hours. Thecooled solution was diluted with water and extracted with ether. Theether extracts were washed with water, 1N hydrochloric acid, water, andsaturated brine and dried over anhydrous sodium sulfate. Solvent removalgave 690 mg. of yellow crystalline solid. This material waschromatographed on 100 g. of Merck silica gel. Elution with 7:2 and 7:3benzene:ether mixtures gave a light yellow solid which was homogenous bythin layer chromatography. Crystallization from acetoneisopropyl ethergave racemic 19-nor-androst-4-ene-3,17-dione as a very pale yellowsolid, m.p. 156.5°-158.5°.

EXAMPLE 11 Preparation oftrans-anti-trans-anti-6-[(3,5-dimethyl-4-isoxazolyl)methyl]-3,3,7,7,-bis(ethylenedioxy)-3a-methyl-perhydro-1H-benz[e]indene

A solution of 654 mg. (2.0 mmoles) of the isoxazole ene dione racemictrans-anti-6-(3,5-dimethyl-4-isoxazolylmethyl)-3a-methyl-1,2,3a,4,5,9,9a,9b-octahydro-3H-benz(e)indene-3,7(8H)-dioneprepared as described above, in 50 ml. of 3:1 ethanol:triethylaminecontaining 60 mg. of 10 per cent palladium on carbon was hydrogenated atatmospheric pressure and room temperature. After 1.0 hr. uptake (1.0equivalent) had ceased. The catalyst was removed by filtration andwashed with fresh ethanol. Solvent removal from the filtrates gave theisoxazole dione, racemictrans-anti-trans-anti-6-[(3,5-dimethyl-4-isoxazolyl)methyl]-3a-methyl-3a,4,5,5a,8,9,9a,9b-octahydro-1H-benz[e]inden-3,7(2H,6H)dione as a colorless foam. This material was taken up in15 ml. of ethylene glycol and 50 ml. of benzene, degassed, and placedunder nitrogen. To the solution was added 400 mg. of p-toluenesulfonicacid monohydrate and the resulting mixture was heated at reflux undernitrogen, with azeotropic removal of water, for 21 hr. After 2 hr.,Linde 3A molecular sieves were placed in the Dean-Stark trap. The palepink solution was extracted with excess saturated aqueous sodiumbicarbonate solution and brine and dried over anhydrous sodium sulfate.Solvent removal at reduced pressure gave the crude isoxazole diketal asa very pale yellow resin.

Pure isoxazole diketal, racemictrans-anti-trans-anti-6-[(3,5-dimethyl-4-isoxazolyl)methyl]-3,3,7,7-bis(ethylenedioxy)-3a-methyl-perhydro-1H-benz[e]indene,was obtained from one such reaction by crystallization of the crudematerial from ether at -20°C.

Anal. Calcd. for C₂₄ H₃₅ NO₅ : C, 69.03; H, 8.45; N, 3.35; O, 19.16.Found: C, 69.34; H, 8.64; N, 3.35.

EXAMPLE 12 Preparation of racemictrans-anti-trans-anti-3,3,7,7-bis(ethylenedioxy)3a-methyl-6-(3-oxobutyl)perhydro-1H-benz[e]indene

The crude noncrystalline isoxazole diketal racemictrans-anti-trans-anti-6-[(3,5-dimethyl-4-isoxazolyl)methyl]-3,3,7,7-bis(ethylenedioxy)3a-methyl-perhydro-1H-benz[e]indenewhose preparation is described in Example 11 above was dissolved in 40ml. of ethanol containing 1.5 g. of potassium hydroxide and 80 mg. of 10per cent palladium on carbon. The resulting solution was hydrogenated atatmospheric pressure and room temperature, under which conditions uptakeof one equivalent of hydrogen took 4 hr. The catalyst was removed byfiltration and washed with fresh ethanol. The solvent was removed fromthe filtrates until a residue of approximately 10 ml. remained. Thissolution of the vinylogous amide was degassed and placed under nitrogen.A previously degassed 20 per cent aqueous potassium hydroxide solution(50 ml.) was added and the resulting mixture was heated at reflux undernitrogen for 18 hr. The cooled solution was diluted with water andextracted with benzene. The benzene solutions were washed with brine anddried over anhydrous sodium sulfate. Solvent removal gave the desiredoxo diketal as a pale yellow resin.

Crystallization of the product of a similar preparation four times fromether yielded analytically pure racemictrans-anti-trans-anti-3,3,7,7-bis(ethylenedioxy)-3a-methyl-b-(3-oxobutyl)perhydro-1H-benz[e]indeneas fine white needles, m.p. 126.5°-128°. This layer chromatography (1:1benzene-ethyl acetate) showed only one spot.

Anal. Calcd. for C₂₂ H₃₄ O₅ : C, 69.81; H, 9.05; O, 21.14. Found: C,70.11; H, 8.99.

EXAMPLE 13 Preparation of racemic 19-nor-Androst-4-en-3,17-dione

The crude keto diketal, racemictrans-anti-trans-anti-3,3,7,7-bis(ethylenedioxy)-3a-methyl-6-(3-oxobutyl)perhydro-1H-benz[e]indenewhose preparation is described in Example 12 above, was suspended in 30ml. of methanol, degassed, and placed under nitrogen. To the flask wasadded 3 ml. of 4N hydrochloric acid and the resulting solution washeated at reflux under nitrogen for 3 hr. The cooled mixture was dilutedwith water and extracted with benzene. The benzene solutions were washedwith saturated aqueous sodium bicarbonate solution and brine and driedover anhydrous sodium sulfate. Thin layer chromatography (1:1benzene-ethyl acetate) of the solution showed only one very faint spotin addition to that corresponding to authentic19-nor-androst-4-en-3,17-dione. Solvent removal gave pale tan crystalswhich were chromatographed on 25 g. of Silica Gel. The material elutedwith 9:1 and 8:2 benzene-ether mixtures was triturated with refluxingisopropyl ether and then cooled to -20° to give racemic19-nor-androst-4-en-3,17-dione as white prisms, m.p. 157°-159.5°.

EXAMPLE 14 Preparation of racemictrans-anti-6-[(3,5-dimethyl-4-isoxazolyl)methyl]-3,3,7,7-bis(ethylenedioxy)-3a-methyl-2,3,3a,4,6,7,8,9,9a,9b-decahydro-1H-benz[e]indene

A solution of 981 mg. (3.0 mmoles) of the isoxazole ene dione, racemictrans-anti-6-(3,5-dimethyl-4-isoxazolylmethyl)-3a-methyl-1,2,3a,4,5,9,9a,9b,-octahydro-3H-benz(e)indene-3,7(8H)-dione,600 mg. of p-toluenesulfonic acid monohydrate and 15 ml. of ethyleneglycol in 50 ml. of benzene was heated at reflux under nitrogen, withazeotropic removal of water, for 23 hr. After 2.0 hr., Linde 3Amolecular sieves were placed in the Dean-Stark trap. The solution wascooled, washed with excess saturated aqueous sodium bicarbonate solutionand brine and dried over anhydrous sodium sulfate. Solvent removal atreduced pressure gave a colorless resin which was crystallized fromether-hexane to give the desired product, racemictrans-anti-6-[(3,5-dimethyl-4-isoxazolyl)methyl]-3,3,7,7-bis(ethylenedioxy)-3a-methyl-2,3,3a,4,6,7,8,9,9a,9b-decahydro-1H-benz[e]indeneas a white crystalline solid, m.p. 120°-127°. A sample from a similarpreparation was crystallized again from ether-hexane to give theanalytically pure diketal as colorless microprisms of m.p. 127°-129°.

Anal. Calcd. for C₂₄ H₃₃ NO₅ : C, 69.37; H, 8.01; N, 3,37; O, 19.25.Found: C, 69.25; H, 8.25; N, 3.36.

EXAMPLE 15 Preparation of racemictrans-anti-3,3,7,7-bis(ethylenedioxy)-3a-methyl-6-(3-oxobutyl)-2,3,3a,4,6,7,8,9,9a,9b-decahydro-1H-benz[e]indene

A solution of 830 mg. (2.0 mmoles) of the isoxazole ene diketal, racemictrans-anti-6-[(3,5-dimethyl-4-isoxazolyl)methyl]-3,3,7,7-bis(ethylenedioxy)-3a-methyl-2,3,3a,4,6,7,8,9,9a,9b-decahydro-1H-benz[e]indeneprepared as described in Example 14 above, in 40 ml. of ethanolcontaining 2.0 g. of potassium hydroxide and 80 mg. of 10 per centpalladium on carbon was hydrogenated at atmospheric pressure and roomtemperature. Uptake (1.0 equivalent) of hydrogen ceased after 6 hr. Thecatalyst was removed by filtration and washed with fresh ethanol. Thesolvent was removed from the filtrate until a residue of 10 ml.remained. This solution of the vinylogous amide was degassed and placedunder nitrogen. A previously degassed solution (50 ml.) of 20 per centaqueous potassium hydroxide was added and the resulting mixture washeated at reflux for 18 hr. The reaction mixture was then diluted withwater and extracted with benzene. The benzene solutions were washed withbrine and dried over anhydrous sodium sulfate. Solvent removal gave apale yellow resin which was homogenous to thin layer chromatography..

Crystallization of a sample from a similar preparation three times fromisopropyl ether gave racemic trans-anti-3,3,7,7-bis(ethylenedioxy)-3a-methyl-6-(3-oxobutyl)-2,3,3a,4,6,7,8,9,9a,9b-decahydro-1H-benz[e]indeneas cream-white prisms, m.p. 80.0°-83.5°.

Anal. Calcd. for C₂₂ H₃₂ O₅ : C, 70.18; H, 8.57; O, 21.25. Found: C,70.85, 70.69; H, 8.68, 8.51.

EXAMPLE 16 Preparation of racemictrans-anti-3a-methyl-6-(3-oxobutyl)-3a,4,5,9,9a,9b-hexahydro-1H-benz[e]indene-3,7(2H, 8H)-dione

The crude keto ene diketal, racemictrans-anti-3,3,7,7-bis-(ethylenedioxy)-3a-methyl-6-(3-oxobutyl)-2,3,3a,4,6,7,8,9,9a,9b-decahydro-1H-benz[e]indene,whose preparation is described in Example 15 above, was dissolved in 30ml. of 1:1 water-acetic acid, degassed, placed uner nitrogen, and heatedat 90°-100° for 11/2 hr. The pale yellow solution was then cooled,diluted with water, and extracted with benzene. The benzene solutionswere washed with saturated aqueous sodium bicarbonate solution and brineand dried over anhydrous sodium sulfate. Solvent removal at reducedpressure gave 650 mg. of pale yelllow resin. This material wascrystallized three times from ether to give the pure trione, racemictrans-anti-3a-methyl-6-(3-oxobutyl)-3a,4,5,9,9a,9b-hexahydro-1H-benz[e]inden-3,7(2H,8H)-dioneas pale yellow prisms, m.p. 101.5°-103°.

Anal. Calcd. for C₁₈ H₂₄ O₃ : C, 74.97; H, 8.39; O, 16.64. Found: C,74.80, H, 8.54.

EXAMPLE 17 Preparation of (-)7-(3,5-dimethyl-4-isoxazolyl)-5-hydroxy-heptanoic acid lactone

A solution of 5.0 g. (22.4 mmoles) of racemic7-(3,5-dimethyl-4-isoxazolyl)-5-hydroxyheptanoic acid lactone, 7.80 g.(50 mmoles) of (-) menthol and 0.1 g. of p-toluenesulfonic acid in 100ml. of benzene was heated at reflux under nitrogen for 16 hours. Thesolution was cooled and washed with saturated aqueous sodium bicarbonatesolution and brine and dried over anhydrous sodium sulfate. Solventremoval at reduced pressure gave a mixture of diastereomeric esters as apale yellow oil. The desired R ester (the absolute configuration wasdetermined by conversion of this material to (+)19-nor-androst-4-en-3,17-dione) was obtained by preparative vapor phasechromatography. A solution of 2.10 g. of this ester in 50 ml. of3N-aqueous potassium hydroxide was heated at reflux under nitrogen for18 hours. The solution was cooled, extracted with ether, acidified with3N-hydrochloric acid, saturated with sodium chloride and extracted withmethylene chloride. The methylene chloride solutions were washed withbrine and dried over anhydrous sodium sulfate. Solvent removal gave acloudy colorless resin. This crude product was heated to 200°C. at 0.2mm., at which time the desired R-lactone, (-)7-(3,5-dimethyl-4-isoxazolyl)-5-hydroxy-heptanoic acid lactone distilledas a colorless liquid.

EXAMPLE 18 (-)2-(2-(-)-α-phenethylaminoethyl)-6-[2-(3,5-dimethyl-4-isoxazolyl)ethyl]-tetrahydropyran-2-oloxalate

A solution of 22.3 g. (0.1 mole) of racemic7-(3,5-dimethyl-4-isoxazolyl)-5-hydroxy heptanoic acid lactone, preparedas described in Example 7, in 330 ml. of dry tetrahydrofuran was cooledin a dry ice-acetone bath under nitrogen as 85 ml. of a 2 M solution ofvinyl magnesium chloride in tetrahydrofuran was added at such a rate asto keep the temperature at -50° to -55° (15 min.). Stirring wascontinued for 30 min. before the solution was hydrolyzed by the carefuladdition of 11 ml. of methanol. The solution was poured onto ice, 53 g.of ammonium chloride and 16 ml. of acetic acid and extracted with ether.The ether solutions were washed with saturated aqueous sodiumbicarbonate solution and brine and dried over anhydrous sodium sulfate.Solvent removal gave 24.8 g. of crude9-(3,5-dimethyl-4-isoxazolyl)-7-hydroxy-non-1-en-3-one as a yellow oil.This crude vinyl ketone was dissolved in 150 ml. of dry benzene. To thissolution was added 8.56 g. of (-) α-phenethylamine and the resultingmixture was stirred under nitrogen at 45° for 2.0 hr. The mixture wasevaporated to dryness to give the crude Mannich base as 43.2 g. ofyellow oil. This crude Mannich base was taken up in 150 ml. of ether andmixed with a solution of 8.5 g. of oxalic acid in 100 ml. of ether. Theoil which separated was removed and washed with ether. The oil wascrystallized from acetonebenzene to give the desired oxalate as a whitesolid, m.p. 111°-114°. Three further crystallizations frommethanol-ether gave analytically pure (-)2-(2-(-)-α-phenethylaminoethyl)-6-[2-(3,5-dimethyl-4-isoxazolyl)ethyl]tetrahydropyran-2-oloxalate as a white powder, m.p. 118°-120°.

Anal. Calcd. for C₂₄ H₃₄ N₂ O₇ : C, 62.32; H, 7.41; N, 6.06; O, 24.21.Found: C, 62.26; H, 7.38.

EXAMPLE 19 (-)3-[2-(3,5-Dimethyl-4-isoxazolyl)ethyl]-6aβ-methyl-1,2,3,5,6,6a-hexahydrocyclopenta[f][l]benzopyran-7(8H)-one

A solution of 84.0 mg. of 2-methyl-cyclopentane-1,3-dione in 5 ml. oftoluene, 2 ml. of 95% acetic acid and 1 ml. of pyridine was carefullydegassed, placed under nitrogen, and heated at reflux 1 min. To thesolution was added 231 mg. of (-) 2-(2-(-)α-phenethylaminoethyl)-6-[2-(3,5-dimethyl-4-isoxazolyl)ethyl]-tetrahydropyran-2-oloxalate, prepared as described in Example 18, and the resulting mixturewas heated at reflux for 31/2 hr., the last 1/2 hr. with azeotropicremoval of water. The cooled solution was diluted with benzene andwashed with brine, saturated aqueous sodium bicarbonate solution andbrine and dried over anhydrous sodium sulfate. Solvent removal gave abrown oil which was chromatographed on 20 g. of activity III neutralalumina. Elution with hexane-benzene mixtures gave the desired dienolether as pale yellow needles, m.p. 85°-88°. Crystallization of thismaterial from isopropyl ether gave analytically pure (-)3-[2-(3,5-dimethyl-4-isoxazolyl)ethyl]-6aβ-methyl-1,2,3,5,6,6a-hexahydrocyclopenta[f][l]benzopyran-7(8H)-oneas pale yellow needles, m.p. 90°-91.5°.

Anal. Calcd. for C₂₀ H₂₅ NO₃ : C, 73.36; H, 7.70; N, 4.28; O, 14.66.Found: C, 73.29; H, 7.74; N, 4.15.

EXAMPLE 20 (+)trans-anti-6-[(3,5-Dimethyl-4-isoxazolyl)methyl]-3a-methyl-1,2,3a,4,5,9,9a,9b-octahydro-3H-benz[e]indene-3,7-(8H)-dione

A solution of 250 mg. of lithium aluminum hydride in 25 ml. of freshlydistilled tetrahydrofuran was cooled in an ice bath under nitrogen as asolution of 789 mg. of (-) 3-[2-(3,5-dimethyl-4-isoxazolyl)ethyl]-6aβ-methyl-1,2,3,5,6,6a-hexahydrocyclopenta-[f][l]benzopyran-7(8H)-one,prepared as described in Example 19, in 5 ml. of tetrahydrofuran wasadded over 5 min. The mixture was stirred at 0° for 15 min. and thenwithout cooling for an additional 30 min. The reaction mixture wascautiously hydrolyzed at 0° with saturated aqueous sodium sulfatesolution, dried over anhydrous sodium sulfate, and filtered. Solventremoval from the filtrates gave crude3-[2-(3,5-dimethyl-4-isoxazolyl)ethyl]-6aβ-methyl-1,2,3,5,6,6a,7,8-octahydrocyclopenta[f][l]benzopyran-7β-olas a pale orange glass.

The crude alcohol was taken up in 20 ml. of tetrahydrofuran. To thissolution was added 100 mg. of a 5 per cent palladium on carbon catalystand the mixture was hydrogenated at atmospheric pressure and roomtemperature. The uptake of one equivalent of hydrogen took 15 hr.Removal of the catalyst by filtration, followed by solvent removal atreduced pressure gavetrans-3-[2-(3,5-dimethyl-4-isoxazolyl)ethyl]-6a-methyl-1,2,3,5,6,6a,7,8,9,9a-decahydrocyclopenta[f[l]benzopyran-7β-olas a pale orange resin. This crude enol ether was taken up in 20 ml. ofacetone, degassed, and placed under nitrogen. To this solution was added10 ml. of 1N sulfuric acid and the resulting mixture was stirred at roomtemperature for 11/2 hr., poured into saturated aqueous sodiumbicarbonate solution and extracted with chloroform. The chloroformsolutions were washed with saturated aqueous sodium bicarbonate solutionand saturated brine and dried over anhydrous sodium sulfate. Solventremoval gave the crude hemiketal,trans-3-[2-(3,5-dimethyl-4-isoxazolyl)ethyl]-6a-methyl-perhydrocyclopenta[f][l]benzopyran-4a,7b-diolas an orangish-colored foam.

The crude hemiketal was dissolved in 20 ml. of acetone and cooled in anice bath as a solution of 1.5 g. of chromium trioxide in 7.5 ml. of 6Nsulfuric acid was added over 20 min. The resulting suspension wasstirred at 0° for 40 min. and then for an additional 11/2 hr. withoutcooling. It was then poured into water and extracted with benzene. Thebenzene solutions were washed with water, saturated aqueous sodiumbicarbonate solution, and brine and dried over anhydrous sodium sulfate.Solvent removal gave crude trans-4-[3-oxo-5(3,5-dimethyl-4-isoxazolyl)pentyl]1a-methyl-perhydroindan-1,5-dione as a pale orange resin. Thismaterial was taken up in 20 ml. of methanol, degassed and placed undernitrogen. To the flask was added 200 mg. of sodium hydroxide and theresulting dark solution was heated at reflux 2.0 hr., cooled, dilutedwith water, and extracted with benzene. The benzene solutions werewashed with brine and dried over anhydrous sodium sulfate. Solventremoval gave the crude isoxazole ene dione which was chromatographed onneutral alumina, activity III. The material eluted with a 95:5benzene-ether mixture was crystallized from isopropyl ether to give pure(+)trans-anti-6-[(3,5-dimethyl-4-isoxazolyl)methyl]-3a-methyl-1,2,3a,4,5,9,9a,9b-octahydro-3H-benz[e]indene-3,7(8H)-dioneas colorless needles, m.p. 85°-87.5°.

EXAMPLE 21 Preparation of (+)trans-anti-6-[(3,5-dimethyl-4-isoxazolyl)methyl] -3a-methyl-3β-tertiarybutoxy-1,2,3,3a,4,5,8,9,9a,9b-decahydro-7H-benz[e]indene-7-one

In a dry flask, 520 mg. of 55% sodium hydride dispersion was washed withpentane to remove the mineral oil. The sodium hydride was suspended in100 ml. of freshly distilled 1,2-dimethoxyethane and 2.76 g. of (+)trans-anti-3a-methyl-3β-tertiarybutoxy-1,2,3,3a,4,5,8,9,9a,9b-decahydro-7H-benz[e]indene-7-one was addedto the suspension. The mixture was heated at reflux under nitrogen for1.0 hr. A solution of 1.75 g. of 4-chloromethyl-3,5-dimethylisoxazole in20 ml. of 1,2-dimethoxyethane was then added at reflux over a period of41/2 hr. The suspension was heated at reflux an additional 11/2 hr.,cooled, diluted with water, and extracted with benzene. The benzenesolutions were washed with brine and dried over anhydrous sodiumsulfate. The orange resin obtained upon solvent removal waschromatographed on 200 g. of silica gel. The material obtained byelution with 95:5 and 90:10 benzene-ether mixtures was crystallized fromether-hexane to give analytically pure (+) trans-anti-6-[(3,5-dimethyl-4-isoxazolyl)methyl]-3a-methyl-3β-tertiarybutoxy-1,2,3,3a,4,5,8,9,9a,9b-decahydro-7H-benz[e]indene-7-one, m.p.125.5°-126.5°.

Anal. Calcd. for C₂₄ H₃₅ N₁ O₃ : C, 74.76; H, 9.15; N, 3.63; O, 12.45.Found: C, 74.88; H, 9.38; N, 4.67.

EXAMPLE 22 Preparation of (-)trans-anti-6-[(3,5-dimethyl-4-isoxazolyl)methyl]-3a-methyl-3β-hydroxy-1,2,3,3a,4,5,8,9,9a,9b-decahydro-7H-benz[e]indene-7-one

A solution of 1.159 g. of (+)trans-anti-6-[(3,5-dimethyl-4-isoxazolyl)methyl]-3a-methyl-3β-tertiarybutoxy-1,2,3,3a,4,5,8,9,9a,9b-decahydro-7H-benz[e]indene-7-one, preparedas described in Example 21, and 1.1 g. of p-toluenesulfonic acidmonohydrate in 100 ml. of benzene was degassed, placed under nitrogenand heated at reflux for 1.0 hr. The cooled solution was washed withsaturated aqueous sodium bicarbonate solution and brine and dried overanhydrous sodium sulfate. Solvent removal gave a yellowish resin whichwas crystallized from isopropyl ether to give the desired alcohol asfine white needles, m.p. 127°-127.5°.

Anal. Calcd. C₂₀ H₂₇ N₁ O₃ : C, 72.92; H, 8.26; N, 4.25; O, 14.57.Found: C, 73.25; H, 8.49; N, 4.16.

EXAMPLE 23 Preparation of (+)trans-anti-6-[(3,5-dimethyl-4-isoxazolyl)methyl]-3a-methyl-1,2,3a,4,5,9,9a,9b-octahydro-3H-benz[e]indene-3,7(8H)-dione

A solution of 415 mg. of (-)trans-anti-6-[(3,5-dimethyl-4-isoxazolyl)methyl]-3a-methyl-3β-hydroxy-1,2,3,3a,4,5,8,9,9a,9b-decahydro-7H-benz[e]indene-7-one, prepared as described in Example 22, in 25 ml.of acetone was cooled in an ice bath as 1.0 ml. of Jones chromiumtrioxide reagent was added over 5 min. The solution was stirred 10 min.,poured into aqueous sodium bisulfite, and extracted with benzene. Thebenzene solutions were washed with water, saturated aqueous sodiumbicarbonate solution and brine and dried over anhydrous sodium sulfate.Solvent removal gave a colorless foam which, on crystallization fromisopropyl ether, gave analytically pure (+)trans-anti-6-[(3,5-dimethyl-4-isoxazolyl)methyl]-3a-methyl-1,2,3a,4,5,9,9a,9b-octahydro-3H-benz[e]indene-3,7(8H)-dioneas white needles, m.p. 85.5°-87.5°.

Anal. Calcd. for C₂₀ H₂₅ N₁ O₃ : C, 73.36; H, 7.70; N, 4.28; O, 14.66.Found: C, 73.67; H, 7.95; N, 4.15.

EXAMPLE 24 Preparation of (+) 19-nor-androst-4-en-3,17-dione.

A solution of 1.308 g. of (+)trans-anti-6-[(3,5-dimethyl-4-isoxazolyl)methyl]-3a-methyl-1,2,3a,4,5,9,9a,9b-octahydro-3H-benz[e]inden-3,7(8H)-dione,prepared as described above in Example 20, in 100 ml. of 3:1ethanol:triethylamine containing 80 mg. of 10 per cent palladium oncarbon, was hydrogenated at atmospheric pressure and room temperature.After 11/2 hr., the uptake of hydrogen ceased. Filtration, followed bysolvent removal, gavetrans-anti-trans-6-[(3,5-dimethyl-4-isoxazolyl)methyl]-3a-methyl-3a,4,5,5a,8,9,9a,9b-octahydro-1H-benz[e]inden-3,7(2H,6H)-dioneas a colorless foam. This crude product was taken up in 10 ml. ofethylene glycol and 75 ml. of benzene and heated with 750 mg. ofp-toluenesulfonic acid at reflux under nitrogen, with azeotropic removalof water, for 20 hr. The cooled solution was washed with saturatedaqueous sodium bicarbonate solution and brine and dried over anhydroussodium sulfate. Solvent removal gave trans-anti-trans-6-[(3,5-dimethyl-4-isoxazolyl)methyl]-3,3,7,7-bis(ethylenedioxy)-3a-methyl-perhydro-1H-benz[e]indeneas a pale yellow resin. A solution of the crude isoxazole diketal in 100ml. of ethanol containing 2.5 g. of potassium hydroxide and 100 mg. of10 per cent palladium on carbon was hydrogenated at atmospheric pressureand room temperature. The uptake of one equivalent of hydrogen took 5.0hr. The catalyst was removed by filtration and the solvent was removedfrom the filtrates until a residue of approximately 5 ml. remained. Tothis solution of the vinylogous amide was added 150 ml. of 20 per centaqueous potassium hydroxide. The mixture was degassed, placed undernitrogen, heated at reflux under nitrogen for 16 hr., cooled, andextracted with benzene. The benzene solutions were washed with brine anddried over anhydrous sodium sulfate. Solvent removal gavetrans-anti-trans-3,3,7,7-bis-(ethylenedioxy)-3a-methyl-6-(3-oxobutyl)-perhydro-1H-benz[e]indeneas a colorless resin. This material was taken up in 50 ml. of methanol,degassed and placed under nitrogen. To the solution was added 5 ml. of4N-hydrochloric acid and the resulting solution was heated at reflux for3.0 hr. The cooled solution was diluted with water and extracted withbenzene. The benzene solutions were washed with water, saturated aqueoussodium bicarbonate solution and brine and dried over anhydrous sodiumsulfate. Solvent removal gave crude 19-nor-androstene dione as a paletan crystalline solid. Filtration of this material through silica gelwith 9:1 benzene:ether followed by crystallization from acetone-hexanegave (+) 19-nor-androst-4-en-3,17-dione as shiny platelets, m.p.173°-174°.

EXAMPLE 25 Preparation of (+)trans-anti-3a-methyl-6-(3-oxobutyl)-3a,4,5,9,9a,9b-hexahydro-1H-benz[e]inden-3,7(2H,8H)-dione.

A solution of 981 mg. of (+)trans-anti-6-[(3,5-dimethyl-4-isoxazolyl)methyl]-3a-methyl-1,2,3a,4,5,9,9a,9b-octahydro-3H-benz[e]inden-3,7-(8H)-dione,prepared as described in Example 20, and 600 mg. of p-toluenesulfonicacid in 15 ml. of ethylene glycol and 50 ml. of benzene was degassed,placed under nitrogen and heated at reflux with azeotropic removal ofwater, for 23 hr. The cooled solution was washed with excess saturatedaqueous sodium bicarbonate solution and brine and dried over anhydroussodium sulfate. Solvent removal gavetrans-anti-6-[(3,5-dimethyl-4-isoxazolyl)methyl]-3,3,7,7-bis-(ethylenedioxy)-3a-methyl-2,3,3a,4,6,7,8,9,9a,9b-decahydro-1H-benz[e]indeneas a colorless resin. This material was taken up in 60 ml. of ethanolcontaining 3.0 g. of potassium hydroxide and 100 mg. of 10 per centpalladium on carbon and hydrogenated at atmospheric pressure and roomtemperature. Uptake of one equivalent of hydrogen took 6.0 hr. Thecatalyst was removed by filtration and the solvent was removed from thefiltrates until approximately 10 ml. remained. To this solution ofvinylogous amide was added 75 ml. of 20 per cent aqueous potassiumhydroxide and the resulting mixture was heated at reflux under nitrogenfor 18 hours. The cooled mixture was diluted with water and extractedwith benzene. The benzene solutions were washed with brine and driedover anhydrous sodium sulfate. Solvent removal gavetrans-anti-3,3,7,7-bis(ethylenedioxy)-3a-methyl-6-(3-oxobutyl)-2,3,3a,4,6,7,8,9,9a,9b-decahydro-1H-benz[e]indeneas a very pale yellow resin. This material was taken up in 500 ml. of1:1 water-acetic acid, degassed, placed under nitrogen, and heated at90°-100° for 11/2 hr. The solution was cooled, diluted with water andextracted with benzene. The benzene solutions were washed with saturatedaqueous sodium bicarbonate solution and brine and dried over anhydroussodium sulfate. Solvent removal gave crude trione as a pale yellowresin. Crystallization of this material from isopropylether gave (+)trans-anti-3a-methyl-6-(3-oxobutyl)-3a,4,5,9,9a,9b-hexahydro-1H-benz[e]inden-3,7(2H,8H)-dione, m.p. 80°-81.5° .

EXAMPLE 26 Preparation of racemic 19-nor-9β,10α-androst-4-en-3,17-dione

A mixture containing 655 mg. (2.0 mM) of racemictrans-anti-6-(3,5-dimethyl-4-isoxazolylmethyl)-3a-methyl-1,2,3a,4,5,9,9a,9b-octahydro-3H-benz(e)indene-3,7(8H)-dione,250 mg. of 7 percent Pd/BaSO₄, 0.5 ml. of 48 percent HBr and 20 ml. ofethanol was hydrogenated at atmospheric pressure and room temperaturefor a period of 8 hours. The catalyst was removed by filtration andwashed with fresh ethanol. The filtrates were diluted with benzene andwashed twice with brine and once each with sodium bicarbonate and brine.The organic layer was then dried over sodium sulfate and the solventremoved to give 650 mg. of a bone-white solid. This material wasdissolved in approximately 3 ml. of hot benzene to which was addedapproximately 15 ml. of ether and the solution was cooled to 0°C. Afterfiltration there was obtained 430 mg. (65 percent yield) of fine whiteneedles oftrans-anti-cis-anti-6-[(3,5-dimethyl-4-isoxazolyl)methyl]-3a-methyl-3a,4,5,5a,8,9,9a,9b-octahydro-1H-benz[e]inden-3,7(2H,6H)-dione. An analyticalsample was prepared by dissolving a small amount of the aforesaidmaterial in methylene chloride, filtering and removing solvent. Theresidue was crystallized from benzene/ether to give very tiny whiteneedles, m.p. 196°-198.5° .

Anal. Calcd. for C₂₀ H₂₇ NO₃ : C, 72.92; H, 8.26; N, 4.25. Found: C,72.57; H, 8.26; N, 4.13.

A solution containing 658 mg. (2.0 mM) of the above retrodione, 200 mg.of p-toluenesulfonic acid hydrate, 15 ml. of ethylene glycol and 60 ml.of benzene was degassed, placed under a nitrogen atmosphere and heatedat reflux with removal of water for 22 hours. The solution was cooled,diluted with benzene and extracted with saturated aqueous sodiumbicarbonate solution (2×), water (2×) and brine. The organic phase wasdried over sodium sulfate and the solvent removed to give a cream-whitesolid representing crude, racemictrans-anti-trans-cis-anti-6[3,5-dimethyl-4-isoxazolyl)methyl]-3,3,7,7-bis(ethylenedioxy)-3a-methyl-perhydro-1H-benz[e]indene.

The above isoxazolyl diketal was suspended in 40 ml. of ethanolcontaining 1.5 g. of KOH. There was then added 150 mg. of a 5 percentPd/C catalyst and the resulting mixture was hydrogenated at atmosphericpressure and room temperature for approximately 1.5 hours. The catalystwas then removed by filtration and washed with fresh ethanol. Thecombined filtrates were evaporated to yield a residue of about 10 ml. Atotal of 50 ml. of 20 percent aqueous KOH was then added to the residueand the resulting solution was degassed, placed under nitrogen andheated at reflux for 20 hours. The mixture was cooled, poured into waterand extracted with benzene. The benzene extracts were washed with brineand dried over sodium sulfate. Solvent removal gave a cloudy lightyellow resin comprising crude, racemictrans-anti-cis-anti-3,3,7,7-bis(ethylenedioxy)-3a-methyl-6-(3-oxobutyl)perhydro-1H-benz[e]indene.

Crude ketone material was taken up in 20 ml. of dioxane, degassed,placed under a nitrogen atmosphere and cooled in an ice bath. A total of1.0 ml. of 25 percent HCl was then added dropwise over 2 minutes. Themixture was cooled another 5 minutes and was then allowed to stir atroom temperature for 22 hours. The light yellow solution was poured intoexcess saturated aqueous sodium bicarbonate solution and extracted withbenzene. The combined benzene solutions were washed with sodiumbicarbonate, brine and then dried over sodium sulfate. Solvent removalgave 603 mg. of light orange resin which crystallized slowly. Thismaterial was chromatographed on silica gel and crystallized fromapproximately 10 ml. of methylenechloride/ether and cooling to -20° togive 272 mg. (50 percent yield) of small white prisms which exhibitedslight melting at 141°-142°; m.p. 148°-152°. Recrystallization fromapproximately 5 ml. of methylene chloride/ether with cooling at -20°gave 239 mg. of small white prisms, m.p. 148.5°-152° (softening at 142°)representing pure 19-nor-9β,10α-androst-4-en-3,17-dione.

Anal. Calcd. C₁₀ H₂₄ O₂ : C, 79.37; H, 8.88. Found: C, 79.07; H, 8.88.

EXAMPLE 27 Preparation oftrans-anti-cis-anti-6-[(3,5-dimethyl-4-isoxazolyl)-methyl]-3,3,7,7-bis(ethylenedioxy)-3a-methyl-perhydro-1H-benz[e]indene

A mixture containing 2.4 g. (7.3 mM) of racemictrans-anti-cis-anti-6-[(3,5-dimethyl-4-isoxazolyl)methyl]-3a-methyl-3a,4,5,5a,8,9,9a,9b-octahydro-1H-benz[e]inden-3,7(2H,6H)dione,600 mg. of p-toluenesulfonic acid hydrate, 25 ml. of ethylene glycol and150 ml. of benzene was degassed, placed under nitrogen and heated atreflux with azeotropic removal of water for 22 hours. The resultingsolution was cooled, washed with saturated aqueous sodium bicarbonate,water (2x) and brine. The organic phase was dried over sodium sulfateand the solvent removed to give 3.1 g. of a white solid. This materialwas dissolved in approximately 5 ml. of methylene chloride/1 percenttriethylamine. To this solution was added 50 ml. of ether. After coolingto -20° there was obtained 2.805 g. of shiny pale yellow prisms, m.p.186°-9° (fast heating). Recrystallization from 6 ml. of methylenechloride/1 percent triethylamine plus 50 ml. of ether with cooling to 0°gave 1.85 g. of colorless prisms, m.p. 188.5°-191° representing pure,racemictrans-anti-cis-anti-6-[(3,5-dimethyl-4-isoxazolyl)methyl]-3,3,7,7-bis(ethylendioxy)-3a-methyl-perhydro-1H-benz[e]indene.

Anal. Calcd. for C₂₄ H₃₅ O₅ N: C, 69.03; H, 8.45; N, 3.35. Found: C,69.14; H, 8.32; N, 3.27.

EXAMPLE 28 Preparation of (-)-19-nor-9β,10α-androst-4-en-3,17-dione

A mixture containing 655 mg. (2.0 mM) of(+)-trans-anti-6-(3,5-dimethyl-4-isoxazolylmethyl)-3a-methyl-1,2,3a,4,5,9,9a,9b-octahydro-3H-benz[e]inden-3,7(8H)-dione, 10 percent Pd/BaSO₄, 1.0 ml. of 47percent HBr and 40 ml. of ethanol was hydrogenated at atmosphericpressure and room temperature for about 5 1/2 hours. The catalyst wasremoved by filtration and washed with fresh ethanol. The combinedfiltrate was eluted with benzene, washed with water, brine, saturatedaqueous sodium bicarbonate solution and then with brine. The organiclayers were dried over sodium sulfate and the solvent removed to yield apale yellow resin which crystallized upon standing. After chromatographyon silica gel the product was dissolved in 2 ml. of methylenechlorideand 20 ml. of ether was added. After seeding and cooling to -20° therewas obtained 295 mg. (45 percent yield) of fine white needles, m.p.169°-172.5° with some previous slight softening. An analytical sample ofpure (+)-trans-anti-cis-anti-6-[(3,5-dimethyl-4-isoxazolyl)methyl]-3a-methyl-3a,4,5,5a,8,9,9a,9b-octahydro-1H-benz[e]inden-3,7(2H,6H)-dionewas obtained by recrystallization from methylene chloride/ether withcooling to 0°, m.p. 170.5°-174°.

Anal. Calcd. for C₂₀ H₂₇ O₃ N: C, 72,92; H, 8.26; N, 4.25. Found: C,72.80; H, 8.40; N, 4.14. [α]_(D) ²⁵ = +122.9° (c = 0.895, CHCl₃) U.V. =λ_(max) = 222 mμ (ε = 4,750).

A solution containing 1.730 g. (5.25 mM) of the above dione and 400 mg.of p-toluenesulfonic acid hydrate in 25 ml. of ethylene glycol and 100ml. of benzene was degassed, placed under nitrogen and heated at refluxwith azeotropic removal of water for 22 hours. The cooled solution waswashed with saturated aqueous sodium bicarbonate (2×), water (2×) andbrine. The organic phase was dried over sodium sulfate and the solventremoved after filtration to give a pale yellow resin as a residue. Theresin comprising(-)-trans-anti-cis-anti-6-[(3,5-dimethyl-4-isoxazolyl)-methyl]-3,3,7,7-bis(ethylenedioxy)-3a-methyl-perhydro-1H-benz[e]-indenewas dissolved in 80 ml. of ethanol containing 3.5 g. of KOH and therewas then added to this solution a total of 400 mg. of 5 percent Pd/Ccatalyst. The resulting mixture was hydrogenated at atmospheric pressureand room temperature. Uptake of hydrogen ceased after about 11/2 hours.The catalyst was removed by filtration and washed with fresh ethanol.The combined ethanol filtrates were stripped of solvent until a residueof approximatley 25 ml. remained.

To this solution of vinylogous amide was added 80 ml. of 20 percentaqueous KOH and the resulting mixture was degassed placed under nitrogenand heated at reflux for 12 hours. The cooled solution was poured intowater and extracted with benzene. The combined benzene extracts werewashed with water and brine. The organic phase was dried over sodiumsulfate and the solvent removed to give crude keto diketal as a yellowresin. The material was taken up in 50 ml. of dioxane, degassed andplaced under nitrogen. The solvent was cooled in an ice bath and whenthe solvent began to solidify a total of 3.0 ml. of 25 per cent HCl wasadded dropwise over three minutes. The mixture was stirred at 0° for anadditional 10 minutes and then at room temperature for 22 hours. Themixture was then diluted with benzene and then washed with water, brine,saturated aqueous sodium bicarbonate and then brine again. The organicphase was dried over sodium sulfate and the solvent removed to yield ayellow resin. The crude steroid was purified by chromatography oversilica gel followed by crystallization from acetone/isopropyl ether 1:10with cooling to -20° to yield (-)-19-nor-9β,10α-androst-4-en-3,17-dioneas white needles, m.p. 131°-135.5°. Recrystallization fromacetone/isopropyl ether as above gave white needles of pure product,m.p. 132°-135.5°.

Anal. Calcd. for C₁₈ H₂₄ O₂ : C, 79.37; H, 8.88 Found: C, 79.24; H,8.87. [α]_(D) ²⁵ = -23.9° (c = 1.055, CHCl₃) U.V. λ_(max) = 239-240 mμ(ε = 17,300).

EXAMPLE 29 Preparation of(-)-trans-anti-cis-anti-6-[(3,5-dimethyl-4-isoxazolyl)methyl]-3,3,7,7-bis(ethylenedioxy)-3a-methyl-perhydro- 1H-benz[e]indene

A mixture containing 1.76 g. (5.33 mM) of(+)-trans-anti-cis-anti-6-[(3,5-dimethyl-4-isoxazolyl)methyl]-3a-methyl-3a,4,5,5a,8,9,9a,9b-octahydro-1H-benz[e]inden-3,7(2H,6H)-dione,400 mg. of p-toluenesulfonic acid hydrate, 15 ml. of ethylene glycol and100 ml. of benzene was degassed, placed under nitrogen and heated atreflux with azeotropic removal of water for 22 hours. The cooledsolution was washed with saturated aqueous sodium bicarbonate (2×),water (2×) and brine. The organic phase was dried over sodium sulfateand then the solvents removed to give 2.34 g. of a colorless glass whichsoon crystallized. Crystallization from acetone/isopropyl ether aftercooling to -20° gave 2.03 g. of white needles, m.p. 155°-158°.Recrystallization from methylene chloride/isopropyl ether with coolingto -20° gave 1.775 g. of fine white needles, m.p. 156°-158.5° of theabove-captioned product.

Anal. Calcd. for C₂₄ H₃₅ NO₅ : C, 69.03; H, 8.45; N, 3.35. Found: C,68.93; H, 8.47; N, 3.36. [α]_(D) ²⁵ = 31.6° (c = 0.87 CHCl₃) U.V.λ_(max) = 223-224 mμ (ε = 4,900).

EXAMPLE 30 Preparation of racemic 19-nor-9β,10α-androst-4-en-3,17-dionevia tricyclic triketone

A suspension containing 725 mg. (1.92 mM) oftrans-anti-cis-anti-3,3,7,7-bis(ethylenedioxy)-3a-methyl-6-(3-oxobutyl)-perhydro-1H-benz[e]indenein 30 ml. of 1:1 acetic acid/water was degassed, placed under nitrogenand heated at 95° for 1 1/2 hour. The cooled mixture was poured intowater and the resulting mixture was extracted with benzene. The combinedbenzene extracts were washed with brine, saturated sodium bicarbonatesolution and brine again. The organic phase was dried over sodiumsulfate and after removal of the solvent there was obtained a paleyellow resin comprising crude racemic,trans-anti-cis-anti-3a-methyl-6-(3-oxobutyl)-perhydro-1H-benz[e]inden-3,7-dione.This material as taken up in 25 ml. of 2-methoxyethanol and 1.01 ml. ofpyrrolidine was added. The mixture was degassed, placed under nitrogenand heated at 95°-100° for 16 hours. A total of 10 ml. of acetate bufferwas added and heating was continued for an additional 2 hours. Themixture was poured into water and extracted with benzene. The benzenesolutions were washed with brine, saturated aqueous bicarbonate andbrine and dried over sodium sulfate. Removal of the solvents gave alight brown resin which crystalized on standing. This resin waschromatographed on silica gel using benzene/ether 8:2 as eluent yieldedthe above-captioned product as light orange crystals. Recrystallizationfrom methylene chloride/ether with cooling to -20° yielded light yellowprisms, m.p. 147°-151° (softening at 138°).

EXAMPLE 31 Preparation of racemic 13-ethyl-9β,10α-gon-4-en-3,17-dione

A mixture containing 1.032 g. (3.0 mM) of racemictrans-anti-3a-ethyl-1,2,3a,4,5,9,9a,9b-octahydro-3H-benz[e]inden-3,7(8H)-dione(prepared in analogous fashion to that described in Examples 8 and 9with the exception that 2-ethylcyclopentane-1,3-dione was employedinstead of the corresponding methyl compound), 300 mg. of 10 percentPd/BaSO₄ and 60 ml. of ethanol was stirred at room temperature for 50minutes. A total of 1.5 ml. of 45 percent HBr was then added and theresulting mixture was hydrogenated at atmospheric pressure and roomtemperature for a period of about 6 1/2 hours at which time uptake ofhydrogen ceased. The catalyst was removed by filtration and washed withfresh ethanol. The combined ethanol filtrates were diluted with benzene,washed with water and brine, saturated aqueous sodium bicarbonatesolution and then with brine again. The organic phase was dried oversodium sulfate and the solvent removed to give 1.043 g. of a whitesolid. This material was chromatographed on silica gel first usingbenzene/ether at 8:2 and finally at 7:3. The latter eluates werecombined and evaporated to give 956 mg. of a white slid which oncrystallization from methylene chloride/ether 1:10 and cooling to -20°gave 781 mg. of fine white needles, m.p. 174°-176.5° (sint. 160°-162°).Recrystallization with the same procedure gave 752 mg. (72 percentyield) of pure, racemictrans-anti-cis-anti-6-[(3,5-dimethyl-4-isoxazolyl)methyl]-3-a-ethyl-3a,4,5,5a,8,9,9a,9b-octahydro-1H-benz[e]inden-3,7(2H,6H)-dione.

A solution containing 2.748 (8.0 mM) of the above isoxazolyl dione and600 mg. of p-toluenesulfonic acid hydrate in 25 ml. of ethylene glycoland 100 ml. of benzene was degassed, placed under nitrogen and heated atreflux with azeotropic removal of water for 22 hours. The mixture wascooled, washed with saturated aqueous sodium bicarbonate (2×), water(2×), and brine. The organic phase was dried over sodium sulfate and thesolvents removed to yield a white crystaline solid comprising racemictrans-anti-cis-anti-6-[(3,5-dimethyl-4-isoxazolyl)methyl]-3,3,7,7-bis(ethylenedioxy)-3a-ethyl-perhydro-1H-benz[e]indene.

The above crude ketal was suspended in a solution containing 5 g ofsodium hydroxide in 125 ml. of ethanol and 650 mg. of 5 percent Pd/C wasadded. The resulting mixture was hydrogenated at atmospheric pressureand room temperature. After 41/2 hours the uptake of hydrogen hadceased. The catalyst was removed by filtration and washed with freshethanol. The solvent was removed until a residue of approximately 50 ml.remained. To this solution was added 100 ml. of 20 percent aqueoussodium hydroxide and the resulting mixture was degassed, placed undernitrogen and heated at reflux for 16 hours. The resulting mixture waspoured into water and extracted with benzene. The benzene solutions werewashed with water, brine and then dried over sodium sulfate. Removal ofthe solvent gave a yellow resin. This material was taken up in 100 ml.of methanol and 10 ml. of 3N HCl was added. This mixture was degassed,placed under nitrogen and heated at reflux for 4 hours. The mixture wasdiluted with benzene, washed with water (2×), saturated sodiumbicarbonate and brine. The organic phase was dried over sodium sulfateand the solvent removed to give a yellow oily solid.

Chromatography of the above crude retrosteroid on silica gel followed bycrystallization from 25 ml. of acetone with cooling to -20° gave 1.494g. of cream-white prisms, m.p. 197°-206.5°. Recrystallization from 25ml. of acetone with cooling to -20°, gave 1.349 (59 percent yield) ofsmall, colorless prisms m.p. 203°-207.5°. An analytical sample of theproduct 13-ethyl-9β,10α-gon-4-en-3,17-dione was obtained by a furthercrystallization from acetone as before to yield a material melting at203.5°-207°.

Anal. Calcd. for C₁₉ H₂₆ O₂ : C, 79.68; H, 9.15. Found: C, 79.69; H,9.12. U.V. - λ_(max) = 240 mμ (ε = 17,900).

EXAMPLE 32 Preparation of racemictrans-anti-cis-anti-6-[(3,5-dimethyl-4-isoxazolyl)methyl]-3,3,7,7-bis(ethylenedioxy)-3a-ethyl-perhydro-1H-benz[e]indene

A total of 1.71 g. (5.0 mM) of racemictrans-anti-cis-anti-6-[(3,5-dimethyl-4-isoxazolyl)methyl]-3a-ethyl-3a,4,5,5a,8,9,9a,9b-octahydro-1H-benz[e]inden-3,7(2H,6H)-dione, 0.5 g. ofp-toluenesulfonic acid hydrate, 20 ml. of ethyleneglycol and 100 ml. ofbenzene was degassed, placed under nitrogen and heated at reflux withazeotropic removal of water for 21 hours. The mixture was cooled, washedwith sodium bicarbonate solution (2×), water (2×) and brine. The organicphase was dried over sodium sulfae and the solvent removed to give awhite solid. Crystallization from approximately 25 ml. of methylenechloride/ether with cooling to -20° gave 1.836 g. of small white prismsmelting at approximately 181°-185°. Recrystallization from approximately10 ml. of the same solvent with cooling to 0° gave 1.49 g. of smallwhite prisms, melting at 183°-186.5° of the above-captioned product.

Anal. Calcd. for C₂₅ H₃₇ O₅ N: C, 69.57; H, 8.64; N, 3.25. Found: C,69.55; H, 8.69; N, 3.20.

We claim:
 1. A compound of the formula ##SPC26##wherein Z" is selectedfrom the group consisting of lower-alkylenedioxy-methylene, di-loweralkoxy-methylene, phendioxy-methylene and a group of the formula##EQU1## wherein R₇ is selected from the group consisting of hydrogen,lower alkyl, lower alkoxy-lower alkyl, tetrahydropyranyl, lower alkanoyland benzoyl; R₈ is selected from the group consisting of hydrogen andlower aliphatic hydrocarbyl; R₁ is a primary alkyl group of from 1 to 5carbons; m is an integer having a value of 1 or 2; R₁₅ is selected fromthe group consisting of lower alkyl and hydrogen; R₁₆ is selected fromthe group consisting of lower alkyl, lower alkylphenyl, phenyl loweralkyl and hydrogen.
 2. The compound as in claim 1 wherein m is 1; R₁ ismethyl or ethyl; R₁₅ and R₁₆ are each independently lower alkyl; Z" islower alkylenedioxy-methylene or a group of the formula ##STR11## R₈ ishydrogen; R₇ is lower alkyl, lower alkanoyl, benzoyl or hydrogen: andthe configuration is trans-anti-trans.
 3. The compound as in claim 2wherein m is 1; R₁ is methyl or ethyl; R₁₅ and R₁₆ are eachindependently lower alkyl; Z" is lower alkylenedioxy-methylene or agroup of the formula ##STR12## R₈ is hydrogen; R₇ is lower alkyl, loweralkanoyl, benzoyl or hydrogen; and the configuration is trans-anti-cis.4. A compound as in claim 2 which istrans-anti-trans-6-[(3,5-dimethyl-4-isoxazolyl)-methyl]-3,3,7,7-bis(ethylenedioxy)-3a-methyl-perhydro-1H-benz[e]indene.5. A compound as in claim 3 which istrans-anti-cis-6-[(3,5-dimethyl-4-isoxazolyl)-methyl]-3,3,7,7-bis(ethylenedioxy)-3a-methyl-perhydro-1H-benz[e]indene.6. A compound as in claim 3 which istrans-anti-cis-6-[(3,5-dimethyl-4-isoxazolyl)-methyl]-3,3,7,7-bis(ethylenedioxy)-3a-ethyl-perhydro-1H-benz[e]indene.